Tyrosine kinase inhibitor compositions, methods of making and methods of use

ABSTRACT

The present disclosure relates to new compounds or pharmaceutically acceptable salts or stereoisomers thereof of formula Ias inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of cancer in mammals (e.g. humans).

RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Application Nos. 62/903,592, filed Sep. 20, 2019, and 62/736,293, filedSep. 25, 2018, the entire contents of each of which are incorporatedherein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to new compounds as inhibitors ofreceptor tyrosine kinases (RTK), in particular oncogenic mutants ofErbB-receptors. The present disclosure also relates to methods ofpreparation these compounds, compositions comprising these compounds,and methods of using them in the treatment of abnormal cell growth inmammals (e.g., humans).

BACKGROUND

Mutations affecting either the intracellular catalytic domain orextracellular ligand binding domain of an ErbB receptor can generateoncogenic activity (the ErbB protein family consists of 4 membersincluding ErbB-1, also named epidermal growth factor receptor (EGFR) andErb-2, also named HER2 in humans). ErbB inhibitors are a known treatmentfor a number of cancers. However, not every patient is responsivesatisfactorily to this treatment. Thus, there is a long-felt need in theart for new therapies that are able to address the variableresponsiveness of cancer patients to known therapies. The presentdisclosure provides compositions and methods for treating cancer inpatients with these oncogenic mutations without the variableresponsiveness observed when patients having these ErbB mutants aretreated using the existing standard of care.

SUMMARY

In some aspects, the present disclosure is directed towards a compoundor pharmaceutically acceptable salts or stereoisomers thereof of formulaI

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Y² is a covalent bond, —O—, —NH—, —NCH₃—, or —C≡C—;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3-6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3-6-membered heteroaryl or 3-9-memberedheterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃ andX is a group of formula (i)a

wherein X¹ is —O—, —CH₂—, —NH—, —S—; Ar¹ is 6 membered aryl orN-heteroaryl, which is unsubstituted or substituted with one or more ofa group selected from hal, C₁₋₆alkyl or C₁₋₆alkoxy; Ar² is 6 memberedaryl or N-heteroaryl, which is unsubstituted or substituted with one ormore of a group selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, —CF₃ or—OCF₃; L¹ is a covalent bond or straight or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal.

In some embodiments substituent Z-L-Y₂ contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is selected from a covalent bond, —CH₂— or—CH(CH₃)—, CH(hal)-, —CH₂—CH₂— or —CH₂—CH(CH₃)—, —CH₂—CH(hal)-.

In some embodiments, X¹-L¹ is —O—, —NH—, —S—, —CH₂—, —O—CH₂—, —NH—CH₂—,—S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—, —NH—CH(CH₃)—,—S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-, or —S—CH(hal)-.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, Ar₁ of the compound of formula (i)a orpharmaceutically acceptable salts or stereoisomers thereof is a group offormula (i)b

wherein X², X^(2′), X⁴, X^(4′) are independently of each other —N═ or—CH═; R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃,with the proviso that at least two of X², X^(2′), X⁴, X⁴ are —CH═;and/or wherein Ar₂ of the compound of formula (i)a or pharmaceuticallyacceptable salts or stereoisomers thereof is a group of formula (i)c

wherein X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other —N═,—CH═; R³, R^(3′) are independently of each other H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃,with the proviso that at least two of X³, X^(3′), X⁵, X^(5′), X⁶ are—CH═.

In some embodiments, group X is a group of formula (ii)a,

wherein X¹ is —O—, —CH₂—, —NH—, —S—; L¹ is a covalent bond or C₁₋₃alkyl,which is unsubstituted or substituted with —CH₃, hal; X², X^(2′), X³,X^(3′), X⁵, X^(5′), X⁶ are independently of each other —N═, —CH═; andR², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃.

In some embodiments, group X is a group of formula (ii)b, (e.g. (ii)b-1or (ii)b-2), or (ii)c, (e.g. (ii)c-1 or (ii)c-2):

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═, —CH═; R², R^(2′), R³, R^(3′), are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃, and n is 0, 1, 2, 3.

In some embodiments, (i) X² and X^(2′) are —CH═ or (ii) X² is —CH═ andX^(2′) is —N═ or X^(2′) is —CH═ and X² is —N═ or (iii) or X² and X^(2′)are —N═.

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g., H, —CH₃, F, and Cl) and/or R³ and R^(3′) areindependently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, —(NR⁶R⁷), —(CR⁶R⁷) are selected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl; X⁴is H, —CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl; and X⁵ is —O—, —NH— or—N(CH₃)—, —SO₂.

In some embodiments, the compound of formula I is not any of

wherein Q is

In some embodiments, the compound of the present disclosure orpharmaceutically acceptable salts or stereoisomers thereof has formulaformula II or III

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Y² is a covalent bond, —O—, —NH—, —NCH₃—, —C≡C—;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3-6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3-6-membered heteroaryl or 3-9-memberedheterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H) and R_(e) is H or methyl; andX is a group of formula (ii)a

wherein X¹ is —O—, —CH₂—, —NH—, —S—; L¹ is a covalent bond or C₁₋₃alkyl,which is unsubstituted or substituted with —CH₃, hal; X², X^(2′), X³,X^(3′), X⁵, X^(5′), X⁶ are independently of each other —N═, —CH═; R²,R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃.

In some embodiments substituent Z-L-Y₂ contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, the compound of formula II is not any of

wherein Q is

In some embodiments, the compound of the present disclosure orpharmaceutically acceptable salts or stereoisomers thereof has formulaIV

whereinX², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═, —CH═;X¹ is —O—, —CH₂—, —NH—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃; andR², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁶R⁷)— or —(CHR⁶R⁷)—, wherein R⁶ and R⁷ form together with theatom to which they are attached to 3-6-membered heteroaryl or3-9-membered heterocycloalkyl, wherein the 3-9-membered heterocycloalkylis a monocycle or a fused, bridged or spirobicycle or a combinationthereof, and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′,—NR′R″, wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, the compound of the present disclosure orpharmaceutically acceptable salts or stereoisomers thereof has formulaVII

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═, —CH═;X¹ is —O—, —CH₂—, —NH—, —S—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3-6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3-6-membered heteroaryl or 3-9-memberedheterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R⁶ and R⁷ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, the compound of formula VII is not any of

wherein Q is

In some embodiments, the compound of the present disclosure orpharmaceutically acceptable salts or stereoisomers thereof has formula X

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═, —CH═;X¹ is —O—, —CH₂—, —NH—, —S—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted to with hal,R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;

R′″ is H or —CH₃;

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl cylobutyl, 3-6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3-6-membered heteroaryl or 3-9-memberedheterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, the compound of the present disclosure orpharmaceutically acceptable salts or stereoisomers thereof has formulaXIII

whereinX², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N—, —CH—;X¹ is —O—, —CH₂—, —NH—, —S—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CH═CH₂, —C≡CH or —C≡C—CH₃; andR², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, or —(NR⁶R⁷)— or —(CHR⁶R⁷)—, wherein R⁶ and R⁷ form together withthe atom to which they are attached to 3-6-membered heteroaryl, or3-9-membered heterocycloalkyl, wherein the 3-9-membered heterocycloalkylis a monocycle, fused bicycle, spirobicycle or a combination thereof, orbridged bicycle, which is unsubstituted or substituted with C₁₋₄ alkyl,hal, —OR′, —NR′R″, wherein R′, R″ are independently of each other H or—C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, —(NR⁶R⁷), —(CHR⁶R⁷) are selected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂; and R^(d) isH, C₁₋₄ alkyl.

The disclosure provides a composition comprising a compound of thedisclosure or pharmaceutically acceptable salts or stereoisomersthereof. In some embodiments, the composition further comprises apharmaceutically acceptable carrier. In some embodiments, thecomposition further comprises a second therapeutically active agent. Insome embodiments, the second therapeutically active agent comprises anon-Type I inhibitor. In some embodiments, the non-Type I inhibitorcomprises a small molecule Type II inhibitor.

The disclosure provides a composition of the disclosure for use in thetreatment of cancer.

The disclosure provides a use of a composition of the disclosure fortreating cancer, comprising administering to a subject atherapeutically-effective amount of the composition.

The disclosure provides a method of treating cancer in a subject,comprising administering to a subject a therapeutically effective amountof a composition of the disclosure.

In some aspects, the present disclosure is directed to a method ofinhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenicvariant of an EGFR), comprising administering the subject in needthereof a therapeutically effective amount of a compound describedherein.

In some aspects, the present disclosure is directed to a method ofinhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenicvariant of an EGFR), comprising administering the subject in needthereof a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in thesubject; and ii) administering the subject in need of the treatment atherapeutically effective amount of a compound described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in thesubject; and ii) administering the subject in need of the treatment acomposition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in abiological sample from the subject; and ii) administering the subject inneed of the treatment a therapeutically effective amount of a compounddescribed herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in abiological sample from the subject; and ii) administering the subject inneed of the treatment a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein when that at least one oncogenic variant of an ErbB receptordescribed herein is identified as being present in the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a compound described herein when that at least oneoncogenic variant of an ErbB receptor described herein is identified asbeing present in the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein when that at least one oncogenic variant of an ErbB receptordescribed herein is identified as being present in a biological samplefrom the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a composition described herein when that at least oneoncogenic variant of an ErbB receptor described herein is identified asbeing present in a biological sample from the subject.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the inhibition of an oncogenic variant of anErbB receptor (e.g., an oncogenic variant of an EGFR).

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the inhibition of an oncogenic variant of anErbB receptor (e.g., an oncogenic variant of an EGFR).

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in the subject.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in the subject.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in a biological sample from the subject.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in a biological sample from the subject.

In some aspects, the present disclosure is directed to use of a compounddescribed herein in the manufacture of a medicament for inhibiting anoncogenic variant of an ErbB receptor (e.g., an oncogenic variant of anEGFR).

In some aspects, the present disclosure is directed to use of a compounddescribed herein in the manufacture of a medicament for preventing ortreating cancer.

The disclosure provides a method of treating cancer in a subject,comprising administering to a subject a therapeutically effective amountof a composition of the disclosure, wherein the cancer is characterizedby expression of an oncogenic variant of an epidermal growth factorreceptor (EGFR). In some embodiments, the cancer, a tumor or a cellthereof expresses the oncogenic variant of an EGFR. In some embodiments,the oncogenic variant of EGFR is an allosteric variant of EGFR.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is an allostericvariant of EGFR, the oncogenic variant of an EGFR comprises an EGFRvariant III (EGFR-Viii) mutation.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is an allostericvariant of EGFR, the oncogenic variant of an EGFR comprises asubstitution of a valine (V) for an alanine (A) at position 289 of SEQID NO: 1.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is an allostericvariant of EGFR, the oncogenic variant of an EGFR comprises amodification of a structure of the EGFR, wherein the oncogenic variantof an EGFR is a capable of forming a covalently linked dimer, whereinthe covalently linked dimer is constitutively active and wherein thecovalently linked dimer enhances an activity of EGFR when contacted to aType I ErbB inhibitor. In some embodiments, the modification of thestructure of the EGFR comprises a modification of one or more of anucleic acid sequence, an amino acid sequence, a secondary structure, atertiary structure, and a quaternary structure. In some embodiments, theoncogenic variant comprises a mutation, a splicing event, apost-translational process, a conformational change or any combinationthereof. In some embodiments, the modification of the structure of theEGFR occurs within a first cysteine rich (CR1) and/or second cysteinerich (CR2) region of EGFR. In some embodiments, the first cysteine rich(CR1) and/or second cysteine rich (CR2) region of EGFR comprises aminoacid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively.In some embodiments, the oncogenic variant of an EGFR generates aphysical barrier to formation of a disulfide bond within the CR1 and/orthe CR2 region. In some embodiments, the oncogenic variant of an EGFRremoves a physical barrier to formation of a disulfide bond within theCR1 and/or the CR2 region. In some embodiments, the the oncogenicvariant of an EGFR comprises one or more free or unpaired Cysteine (C)residues located at a dimer interface of the EGFR. In some embodiments,the oncogenic variant of an EGFR comprises one or more free or unpairedCysteine (C) residues at a site selected from the group consisting ofC190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248,C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515,C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591,C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. In someembodiments, the modification occurs within 10 angstroms or less of anintramolecular disulfide bond at a site selected from the groupconsisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240,C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333,C506-C515, C510-C523, C526-C535, C539-C555, C558—C571, C562-C579,C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is mutation of EGFR,a nucleotide sequence encoding the oncogenic variant of an EGFRcomprises a deletion or a substitution of a sequence encoding exon 19 ora portion thereof. In some embodiments, the deletion or the substitutioncomprises one or more amino acids that encode an adenosine triphosphate(ATP) binding site. In some embodiments, the ATP binding site comprisesamino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATPbinding site or the deletion or substitution thereof comprises K858 ofSEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ IDNO: 1. In some embodiments, an arginine (R) is substituted for thelysine (K) at position 858 (K858R) of SEQ ID NO: 1. In some embodiments,an arginine (R) is substituted for the leucine (L) at position 858(L858R) of SEQ ID NO: 1.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is an allostericvariant of EGFR, a nucleotide sequence encoding the oncogenic variant ofan EGFR comprises an insertion within a sequence encoding exon 20 or aportion thereof. In some embodiments, the sequence encoding exon 20 or aportion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQID NO: 7). In some embodiments, the sequence encoding exon 20 or aportion thereof comprises a sequence encoding a C-helix, a terminal endof the C-helix or a loop following the C-helix. In some embodiments, theinsertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA.In some embodiments, the sequence encoding exon 20 or a portion thereofcomprises one or more of: (a) an insertion of the amino acid sequenceASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion ofthe amino acid sequence SVD between positions D770 and N771 of SEQ IDNO: 1; (c) an insertion of the amino acid sequence NPH between positionsH773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acidsequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) aninsertion of the amino acid sequence PH between positions H773 and V774of SEQ ID NO: 1; (f) an insertion of the amino acid G between positionsD770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid Hbetween positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of theamino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1;(i) an insertion of the amino acid sequence AH between positions H773and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequenceSVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitutionof the amino acid sequence GYN for the DN between positions 770 and 771of SEQ ID NO: 1; (l) an insertion of the amino acid H between positionsN771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Ybetween positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of theamino acid sequence PHVC between positions C775 and R776 of SEQ ID NO:1; (o) a substitution of the amino acid sequence YNPY for the H atposition 773 of SEQ ID NO: 1; (p) an insertion of the amino acidsequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) aninsertion of the amino acid sequence VDS between positions S768 and V769of SEQ ID NO: 1; (r) an insertion of the amino acid H between positionsD770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid Nbetween positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of theamino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1;(u) a substitution of the amino acid sequence GSVDN for the DN betweenpositions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the aminoacid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO:1; (w) an insertion of the amino acid G between positions N771 and P772of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP betweenpositions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the aminoacid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) asubstitution of the amino acid sequence GNPHVC for the VC betweenpositions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the aminoacid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb)an insertion of the amino acid sequence GL between positions D770 andN771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y betweenpositions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the aminoacid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee)an insertion of the amino acid sequence TH between positions H773 andV774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGPfor the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) asubstitution of the amino acid sequence SVDNP for the NP betweenpositions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the aminoacid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii)an insertion of the amino acid T between positions N771 and P772 of SEQID NO: 1; and (j) a substitution of the amino acid sequence STLASV forthe SV between positions 768 and 769 of SEQ ID NO: 1.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein the cancer is characterized by expression of anoncogenic variant and the oncogenic variant of EGFR is an allostericvariant of EGFR, the oncogenic variant of an EGFR comprises EGFR-Vii,EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P,EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R,EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D,EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C,EGFR-A660, EGFR-A768 or any combination thereof.

The disclosure provides a method of treating cancer in a subject,comprising administering to a subject a therapeutically effective amountof a composition of the disclosure, wherein the cancer is characterizedby expression of one or more of: (a) a wild type human epidermal growthfactor receptor 2 (HER2) receptor or (b) an oncogenic variant of a HER-2receptor. In some embodiments, the cancer, a tumor or a cell thereofexpresses one or more of: (a) a wild type human epidermal growth factorreceptor 2 (HER2) receptor or (b) an oncogenic variant of a HER-2receptor. In some embodiments of the methods of treating cancer of thedisclosure, including those wherein cancer is characterized bycharacterized by expression of a wild type HER2 receptor, the wild typeHER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4,5, or 6.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor, the oncogenic variant of the HER2receptor is an allosteric variant of the HER2 receptor.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of aphenylalanine (F) for a seine (S) at position 310 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of atyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of aglutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of aleucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of amethionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of anisoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of analanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of aproline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises a substitution of aserine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, anucleotide sequence encoding the oncogenic variant of a HER2 receptorcomprises an insertion within a sequence encoding exon 20 or a portionthereof. In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO:8). In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding a C-helix, a terminal end of theC-helix or a loop following the C-helix. In some embodiments, theinsertion comprises the amino acid sequence of GSP or YVMA. In someembodiments, the sequence encoding exon 20 or a portion thereofcomprises one or more of: (a) an insertion of the amino acid sequenceYVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertionof the amino acid sequence GSP between positions P780 and Y781 of SEQ IDNO: 2; (c) an insertion of the amino acid sequence YVMA betweenpositions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the aminoacid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e)an insertion of the amino acid V between positions V777 and G778 of SEQID NO: 2; (f) an insertion of the amino acid V between positions V777and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequenceAVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) asubstitution of the amino acid sequence LC for the G between position776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCVfor the G between position 776 of SEQ ID NO: 2; (j) an insertion of theamino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2;(k) a substitution of the amino acid sequence PS for the LRE betweenpositions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the aminoacid sequence CPGSP for the SP between positions 779 and 780 of SEQ IDNO: 2; (m) an insertion of the amino acid C between positions V777 andG778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMAfor the AG between positions 775 and 776 of SEQ ID NO: 2; (o) asubstitution of the amino acid sequence VV for the G at position 776 ofSEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for theGV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution ofthe amino acid sequence VCV for the GV between positions 776 and 777 ofSEQ ID NO: 2; (r) an insertion of the amino acid G between positionsG778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acidsequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2;(t) an insertion of the amino acid V between positions A775 and G776 ofSEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA betweenpositions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the aminoacid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) asubstitution of the amino acid sequence AVCGG for the GVG betweenpositions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the aminoacid sequence CVCG for the GVG between positions 776 and 778 of SEQ IDNO: 2; (y) a substitution of the amino acid sequence VVVG for the GVGbetween positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of theamino acid sequence SVGG for the GVGS between positions 776 and 779 ofSEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES forthe GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) asubstitution of the amino acid sequence AVGSGV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the aminoacid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO:2; (dd) a substitution of the amino acid sequence HVC for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the aminoacid sequence VAAGV for the GV between positions 776 and 777 of SEQ IDNO: 2; (ff) a substitution of the amino acid sequence VAGV for the GVbetween positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution ofthe amino acid sequence VVV for the GV between positions 776 and 777 ofSEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG betweenpositions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the aminoacid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) asubstitution of the amino acid sequence VPS for the VLRE betweenpositions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the aminoacid E between positions V777 and G778 of SEQ ID NO: 2; (ll) aninsertion of the amino acid sequence MAGV between positions V777 andG778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S betweenpositions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the aminoacid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and(oo) an insertion of the amino acid sequence LMAY between positions Y772and V773 of SEQ ID NO: 2.

In some embodiments of the methods of treating cancer of the disclosure,including those wherein cancer is characterized by expression of anoncogenic variant of a HER2 receptor and wherein the oncogenic variantof the HER2 receptor is an allosteric variant of the HER2 receptor, theoncogenic variant of a HER2 receptor comprises HER2-Δ16 (i.e. a HER2variant that lacks Exon 16), HER2-C311R, HER2-S310F, p95-HER2-M611 (i.e.a HER2 variant wherein the amino acid encoding the protein begins atM611 of a wild type HER2 sequence, including SEQ ID NO: 2) or anycombination thereof.

The disclosure provides a method of treating cancer in a subject,comprising administering to a subject a therapeutically effective amountof the composition of the disclosure, wherein the cancer ischaracterized by expression of an oncogenic variant of a HER-4 receptor.In some embodiments, the oncogenic variant of the HER-4 receptor is anallosteric variant of the HER4 receptor. In some embodiments, theoncogenic variant of a HER4 receptor comprises deletion of exon 16(HER4-A16).

In some embodiments of the methods of treating cancer of the disclosure,the administration is systemic. In some embodiments, the administrationoral. In some embodiments, the administration is intravenous.

In some embodiments of the methods of treating cancer of the disclosure,the administration is local. In some embodiments, the administrationintratumoral, intraocular, intraosseus, intraspinal orintracerebroventricular.

In some embodiments of the methods of treating cancer of the disclosure,the subject or the cancer is insensitive or resistant to treatment withone or more of gefinitinib, erlotinib, afatinib, osimertinib,necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib,afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040,WZ3146, CO-1686 and AZD9291.

In some embodiments of the methods of treating cancer of the disclosure,the subject or the cancer has an adverse reaction to treatment with oneor more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab,crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib,sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146,CO-1686 and AZD9291. In some embodiments, the adverse reaction is anactivation of the oncogenic variant of an EGFR and wherein the oncogenicvariant comprises a mutation in an extracellular domain of the receptor.In some embodiments, the adverse reaction is an activation of theoncogenic variant of a HER-2 Receptor and wherein the oncogenic variantcomprises a mutation in an extracellular domain of the receptor.

In some embodiments of the methods of treating cancer of the disclosure,the cancer, a tumor or a cell thereof expresses an oncogenic variant ofan EGFR, wherein the sequence encoding the oncogenic variant of the EGFRcomprises a deletion of exon 20 or a portion thereof and wherein the thecancer, the tumor or the cell thereof does not comprise a secondoncogenic variation in a sequence other than exon 20 of EGFR. In someembodiments, the second oncogenic variation comprises a sequenceencoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, andKRAS.

In some embodiments of the methods of treating cancer of the disclosure,the cancer, a tumor or a cell thereof expresses an oncogenic variant ofan EGFR, wherein the sequence encoding the oncogenic variant of the EGFRcomprises a deletion of exon 20 or a portion thereof and wherein the thecancer, the tumor or the cell thereof does not comprise a markerindicating responsiveness to immunotherapy.

In some embodiments of the methods of treating cancer of the disclosure,the cancer comprises a solid tumor. In some embodiments, the cancer is abladder cancer, a breast cancer, a cervical cancer, a colorectal cancer,an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a headand neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC) orany subtype thereof. In some embodiments, the cancer is a glioblastoma(GBM) or any subtype thereof. In some embodiments, the cancer is abreast cancer or any subtype thereof. In some embodiments, the cancer isa lung cancer or any subtype thereof.

In some embodiments of the methods of treating cancer of the disclosure,the therapeutically effective amount reduces a severity of a sign orsymptom of the cancer. In some embodiments, the sign of the cancercomprises a tumor grade and wherein a reduction of the severity of thesign comprises a decrease of the tumor grade. In some embodiments, thesign of the cancer comprises a tumor metastasis and wherein a reductionof the severity of the sign comprises an elimination of the metastasisor a reduction in the rate or extent the metastasis. In someembodiments, the sign of the cancer comprises a tumor volume and whereina reduction of the severity of the sign comprises an elimination of thetumor or a reduction in the volume. In some embodiments, the symptom ofthe cancer comprises pain and wherein a reduction of the severity of thesign comprises an elimination or a reduction in the pain.

In some embodiments of the methods of treating cancer of the disclosure,the therapeutically effective amount induces a period of remission.

In some embodiments of the methods of treating cancer of the disclosure,the therapeutically effective amount improves a prognosis of thesubject.

In some embodiments of the methods of treating cancer of the disclosure,the subject is a participant or a candidate for participation in in aclinical trial or protocol thereof. In some embodiments, the subject isexcluded from treatment with a Type I inhibitor. In some embodiments,the Type I inhibitor comprises gefinitinib, erlotinib, afatinib,osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib,trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib,WZ4002, WZ8040, WZ3146, CO-1686 or AZD9291.

In some embodiments of the methods of treating cancer of the disclosure,the method further comprises treating the subject with a Non-Type Iinhibitor.

In some embodiments of the methods of treating cancer of the disclosure,the composition further comprises a Non-Type I inhibitor.

In some embodiments of the methods of treating cancer of the disclosure,the Non-Type I inhibitor comprises a Type II small molecule inhibitor.In some embodiments, the Type II small molecule inhibitor comprisesneratinib, AST-1306, HKI-357, or lapatinib.

The disclosure provides a method of treating cancer in a subjectcomprising administering to the subject a Non-Type I inhibitor or apotent Type I inhibitor, wherein the subject comprises an allostericvariant of an EGFR or an allosteric variant of a HER2-receptor. In someembodiments, the Non-Type I ErbB inhibitor comprises a Type II smallmolecule inhibitor. In some embodiments, the Non-Type I ErbB inhibitoror potent Type I inhibitor comprises AMG-595, rindopepimut, sapitinib,afatinib, neratinib, AST-1306, HKI-357, or lapatinib. In someembodiments, the cancer comprises a solid cancer. In some embodiments,the cancer comprises a bladder cancer, a breast cancer, a cervicalcancer, a colorectal cancer, an endometrial cancer, a gastric cancer, aglioblastoma (GBM), a head and neck cancer, a lung cancer, a non-smallcell lung cancer (NSCLC) or any subtype thereof. In some embodiments,the cancer comprises a glioblastoma (GBM) or any subtype thereof. Insome embodiments, the cancer comprises a breast cancer or any subtypethereof. In some embodiments, the cancer comprises a lung cancer or anysubtype thereof.

BRIEF DESCRIPTION OF FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is an illustration of the structure of EGFR and a group of 20genomic mutations affecting the CR1 or CR2 regions of EGFR and which areexpressed in GBM tumors. Mutations are highlighted within the crystalstructure for the ectodomain of EGFR (1IVO). Mutations are noted asmagenta spheres. EGF ligand is shown in green, and the EGFR protomersare shown in grey and orange. See also Table 2.

FIG. 2 is a schematic depiction of an expression pattern for EGFRsplicing events and mutations in the CR1 and CR2 regions for a group of164 GBM tumors. One tumor, TCGA.878, expressing four variants(EGFR-Viii, EGR-A289T, EGFR-A289V, and EGFR-A289D, is noted. More than65% of GBM tumors express EGFR ectodomain variants affecting the CR1/2regions.

FIG. 3 is a graph depicting exemplary ectodomain variants of ErbBreceptors that are transforming. The proliferation of BaF3 cellsexpressing EGFR-Viii, EGFR-Vii, or EGFR-A289V, or vector alone(parental), cultured in the absence of IL-3. The proliferation ofparental BaF3 cells cultured in the presence of IL-3 is shown as acontrol.

FIG. 4 is an illustration of the structure of EGFR and exemplary freecysteines that are formed at the extracellular dimer interface of EGFRas a result of genomic mutations and alternative splicing events incancer. Arrows note the positions of free cysteines predicted to begenerated as a result of the events EGFR-A289V, EGFR-Viii, EGFR-Vii, andEGFR-Vvi. Positions are mapped onto the crystal structure of theectodomain of EGFR (1 IVO). EGF ligand is shown in green, and EGFRprotomers are shown in grey and orange.

FIG. 5A is a series of photographs of Western blots depicting theexpression of total and phosphorylated monomeric EGFR versus covalentEGFR dimers for EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V, detectedby resolving proteins under non-reducing conditions. The datademonstrate that EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V exist ascovalently activated dimers.

FIG. 5B is a graph depicting the quantitation of results from FIG. 5A,and the quantitation of percentage of receptor that exists as covalentdimer for total versus phosphorylated receptor.

FIG. 6 is a pair of photographs of Western blots depicting the effect ofEGF treatment on levels of monomeric and dimeric phosphorylated EGFR forEGFR-Vii and EGFR-Vvi. In contrast to EGFR-Viii, EGF further potentiatesthe formation of active covalent dimers for EGFR-Vii and EGFR-Vvi.

FIG. 7A is a series of photographs of Western blots depicting the effectof 100 nM erlotinib treatment on levels of monomeric and dimeric EGFRlevels in cells expressing EGFR-Viii, EGFR-Vii, EGFR-Vvi, or EGFR-A289V.Monomeric and dimeric EGFR levels were detected by resolving proteinsunder non-reducing conditions. The data demonstrate that Type Iinhibitors enhance the formation of covalent dimers for allcovalently-activated EGFR variants.

FIG. 7B is a pair of photographs of Western blots depicting the effectof varying concentrations of erlotinib on monomeric and dimeric EGFRlevels in cells expressing EGFR-Vii. Monomeric and dimeric EGFR levelswere detected by resolving proteins under non-reducing conditions.

FIG. 7C is a graph quantifying the data presented in FIG. 7B. The datademonstrate that erlotinib induces a dose dependent increase incovalently dimerized receptor.

FIG. 8 is a series of photographs of Western blots depicting the effectof a panel of Type I and Type II inhibitors on dimeric and monomericEGFR levels for cells expressing EGFR-Vii and EGFR-A289V. Monomeric anddimeric EGFR levels were detected by resolving proteins undernon-reducing conditions. The data demonstrate that Type I, but not TypeII, ErbB inhibitors enhance the formation of covalent dimers forcovalently-activated EGFR variants.

FIG. 9 is a series of photographs of Western blots depicting the effectof 100 nM erlotinib treatment on monomeric and dimeric EGFR levels fortwo EGFR variants. Monomeric and dimeric EGFR levels were detected byresolving proteins under non-reducing conditions. The data demonstratethat both EGFR-A660 and EGFR-A768 can exist as covalent dimers andcovalent dimer is potentiated following treatment with erlotinib.

FIG. 10A is a series of photographs of Western blots depicting theeffect of varying concentrations of erlotinib on monomeric and dimericlevels of phosphorylated EGFR in cells expressing EGFR-Viii, EGFR-Vii,and EGFR-A289V. Monomeric and dimeric EGFR levels were detected byresolving proteins under non-reducing conditions. The data demonstratethat sub-saturating concentrations of erlotinib stimulate thephosphorylation of covalently dimerized splice-activated EGFR isoforms.

FIG. 10B is a series of photographs of Western blots depicting theeffect of varying concentrations of erlotinib treatment, followed by a30 minute washout, on total and phosphorylated EGFR levels in cellsexpressing EGFR-Vii or EGFR-Vvi. Proteins were resolved undernon-reducing conditions. The data demonstrate that erlotinibparadoxically enhances the phosphorylation of covalent dimers forEGFR-Vii and EGFR-Vvi.

FIG. 11A is a graph depicting the effect of DMSO, 37 nM erlotinib, or100 nM erlotinib on the proliferation of BaF3 cells expressingEGFR-Viii. Proliferation data were collected at multiple time pointsover a three day period. The data demonstrate that sub-saturatingconcentrations of erlotinib result in paradoxical stimulation ofproliferation in cells expressing splice-activated EGFR.

FIG. 11B is a graph depicting the effect of varying concentrations oferlotinib on the proliferation of BaF3 cells expressing EGFR-Viii,EGFR-Vii or EGFR-A289V. Proliferation was assessed at 72 hours aftererlotinib dosing. The data demonstrate that sub-saturatingconcentrations of erlotinib paradoxically stimulate the growth of BaF3cells driven by EGFR-Viii, EGFR-Vii, and EGFR-A289V.

FIG. 12 is a series of graphs depicting the effect of 12.5 nM or 1 uM ofWZ8040, WZ3146, or WZ4002 on the proliferation of BaF3 cells expressingEGFR-Viii. Proliferation data were collected at multiple time pointsover a three day period. The data demonstrate that sub-saturatingconcentrations of WZ8040, WZ3146 or WZ4002 result in paradoxicalstimulation of proliferation in cells expressing EGFR-Viii.

FIG. 13A is an illustration of the structure of EGFR and exemplary freecysteines are formed at the extracellular dimer interface of HER2receptors as a result of genomic mutations and alternative splicingevents in cancer. Arrows point to positions of free cysteines generatedby the A16 splice event or C311R or S310F mutations.

FIG. 13B is a pair of graphs demonstrating that HER2 and HER4 splicevariants are transforming. The proliferation of BaF3 cells expressingHER4-WT (JMA), HER4A16 (JMC), and HER2Δ16, or vector alone (parental),cultured in the absence of IL-3. The proliferation of parental BaF3cells cultured in the presence of IL-3 is shown as a control.

FIG. 14 is a series of photographs of Western blots depicting theexpression of dimeric and monomeric levels of phosphorylated HER2 orHER4 receptors in cells expressing each variant. Monomeric and dimericEGFR levels were detected by resolving proteins under non-reducingconditions. The data demonstrate that multiple HER2 and HER4 splicingevents and mutations in the CR1 and CR2 regions result in covalentlyactive dimers.

FIG. 15A is a series of photographs of Western blots depicting theeffect of the Type I HER2 inhibitor sapitinib or the Type I HER4inhibitor afatinib on levels of dimerized receptors for cells expressingHER2-Δ16, HER2-C311R, HER2-S310F, or HER4Δ16. Monomeric and dimeric HER2and HER4 levels were detected by resolving proteins under non-reducingconditions. The data demonstrate that Type I inhibitors induce theformation of covalent dimers for covalently-activated HER2 and HER4isoforms.

FIG. 15B a series of photographs of Western blots and correspondinggraphs depicting the effect of varying concentrations of sapitinib orafatinib on the levels of dimerized HER2 or HER2 in cells expressingHER2-Δ16 or HER4-A16. Monomeric and dimeric HER2 and HRE4 levels weredetected by resolving proteins under non-reducing conditions. The datademonstrate that Type I inhibitors induce a dose dependent increase incovalently dimerized receptors for HER2 and HER4 variants.

FIG. 16 is a graph depicting the effect of varying concentrations ofsapitinib on the proliferation of BaF3-HER2-Δ16 cells. The datademonstrate that sub-saturating concentrations of the Type I inhibitorsapitinib paradoxically stimulate the proliferation of BaF3-HER2Δ16cells.

FIGS. 17A-C are a series of graphs demonstrating that expression levelsof ErbB splice variants can be measured by isoform selective PCR. Theexpression levels of EGFR-Viii (A), EGFR-Vii (B), and EGFR-Vvi (C) incells engineered to express the respective splice-variant as compared tocells that do not express the respective splice-variant. Primers andprobes used to detect each variant are listed. Primers and probes usedto detect EGFRVIII are identified as SEQ ID NO: 9 (forward), SEQ ID NO:10 (probe) and SEQ ID NO: 11 (reverse). Primers and probes used todetect EGFRVii are identified as SEQ ID NO: 12 (forward), SEQ ID NO: 13(probe) and SEQ ID NO: 14 (reverse). Primers and probes used to detectEGFRVvi are identified as SEQ ID NO: (forward), SEQ ID NO: 16 (probe)and SEQ ID NO: 17 (reverse).

FIG. 18 is a graph showing the fraction of the maximum proliferation ofcells having, for example, the EGFR-Vii mutation with NT-113, a potentType I covalent inhibitor. NT-113 induces dimerization for covalentlyactivated ErbB receptors. In contrast to reversible Type I inhibitors,and other covalent Type I inhibitors, there is no evidence for increasedcellular proliferation in response to NT-113. Therefore, in contrast toreversible Type I inhibitors, and other covalent Type I inhibitors,NT-113 represents a potent Type I covalent molecule that could be usedto treat tumors driven by covalently-activated ErbB receptors.

FIG. 19 is a table providing potency values for representative marketedErbB inhibitors against EGFR and HER2 receptor variants. The data showthat these cpds lack potency and selectivity against allo-HER2mutations. These compounds also lack potency and selectivity againstErbB Exon 20 ins mutants and ErbB Exon 20 deletion mutants. Potencyvalues reflect cellular anti-proliferative activity (IC50, nM).EGFR-WT=A431 (+H292); HER2-WT=BT474; H4006=EGFR19del; all mutants areBaF3 transformants. Green boxes depict greater than a 10-fold selectiveinhibition of oncogenic mutants versus WT-EGFR and red boxes depict lessthan a 10-fold selective inhibition of oncogenic mutants versus WT-EGFR.

FIG. 20 is a table providing potency values for representative marketedErbB inhibitors against EGFR and HER2 receptor variants. The data showthat these cpds lack potency and selectivity against ErbB Exon 20 insmutants and ErbB Exon 20 deletion mutants. Potency values reflectcellular anti-proliferative activity (IC50, nM). EGFR-WT=A431 (+H292);HER2-WT=BT474; H4006=EGFR19del; all mutants are BaF3 transformants.Green boxes depict greater than a 10-fold selective inhibition ofoncogenic mutants versus WT-EGFR and red boxes depict less than a10-fold selective inhibition of oncogenic mutants versus WT-EGFR.

FIG. 21 is a graph showing the effect of Compound No. 6 on growthinhibition in a panel of cell lines harboring HER and EGFR variants.

FIG. 22 is a graph showing the effect of Compound No. 6 on growthinhibition in patient-derived cell lines harboring EGFR mutants.

FIG. 23 is a graph comparing the selectivity of Compound No. 8 and atable summarizing representative selectivity data.

FIG. 24 is a graph showing the effect of Compound No. 8 on growthinhibition in a panel of cell lines harboring HER and EGFR mutants.

FIG. 25 is a diagram of the in vivo potency of Compound No. 8 on variousHER and EGFR mutants.

FIG. 26 is a graph showing the effect of Compound No. 8 on HER mutanttumor volume in vivo.

FIG. 27 is a graph showing the effect of Compound No. 26 on HER mutanttumor volume in vivo.

FIG. 28 is a graph showing the effect of Compound No. 26 on HER mutanttumor volume in vivo under several dosing regimens.

FIG. 29 is a graph showing the effect of Compound No. 21 on HER mutanttumor volume in vivo.

FIG. 30 is a graph showing the effect of Compound No. 6 on HER mutanttumor volume in vivo.

FIG. 31 is a graph showing the effect of Compound No. 8 on HER mutanttumor volume in vivo under several dosing regimens.

FIG. 32 is a graph showing the effect of Compound No. 6 on EGFR mutanttumor volume in vivo under several dosing regimens.

FIG. 33 is a graph showing the effect of Compound No. 26 on tumors withHER mutant signaling and corresponding Compound No. 26 plasma levels invivo.

FIG. 34 is a graph showing the effect of Compound No. 21 on tumors withHER mutant signaling and corresponding Compound No. 21 plasma levels invivo.

FIG. 35 is a graph showing the effect of Compound No. 5 on tumors withHER mutant signaling and corresponding Compound No. 5 plasma levels invivo.

FIG. 36 is a graph showing the effect of Compound No. 118 on tumors withHER mutant signaling and corresponding Compound No. 118 plasma levels invivo.

FIG. 37 is a graph showing the effect of Compound No. 27 on tumors withHER mutant signaling and corresponding Compound No. 27 plasma levels invivo.

DETAILED DESCRIPTION

The present disclosure relates to new compounds useful as inhibitors ofreceptor tyrosine kinases (RTK), including oncogenic mutants ofErbB-receptors. In some embodiments of the present disclosure, oncogenicmutants of ErbB-receptors are also allosteric mutants of ErbB-receptors.In some embodiments of the present disclosure, allosteric mutants maycomprise or consist of an ErbB receptor variant having a mutation in asequence outside of an ATP-binding site. In some embodiments of thepresent disclosure, allosteric mutants may comprise or consist of anErbB receptor variant having a mutation in a sequence within one or moreof exon 19, exon 20 or a C1-C2 extracellular dimerization interface.

Mutations affecting either the intracellular catalytic domain orextracellular ligand binding domain of an ErbB receptor can generateoncogenic activity (the ErbB protein family consists of 4 membersincluding ErbB-1, also named epidermal growth factor receptor (EGFR) andErb-2, also named HER2 in humans). Extracellular mutants of ErbBreceptors in cancer, including EGFR-Viii (also EGFR-V3) and HER2-S310F,are constitutively activated in the absence of ligand, exhibit sustainedsignaling that is resistant to downregulation, and are both transformingand tumorigenic (Nishikawa, Ji et al. 1994, 2013, Francis, Zhang et al.2014). Their expression is associated with metastasis and with poor longterm overall survival.

In glioblastoma (also glioblastoma multiforma or GBM), EGFR-Viii isexpressed by 20% of tumors (Sugawa, Ekstrand et al. 1990, Brennan,Verhaak et al. 2013). Expression of EGFR-Viii in GBM tends to bemutually exclusive with expression of other RTK oncogenes, which areco-expressed with EGFR variants in only 7% of GBM tumors (Furnari,Cloughesy et al. 2015). These data demonstrate how EGFR-Viii in GBM hasa dominant and mutually exclusive expression pattern compared with otheroncogenic drivers. EGFR-Viii is also expressed by approximately 30% ofSCCHN tumors (Sok, Coppelli et al. 2006, Keller, Shroyer et al. 2010,Wheeler, Suzuki et al. 2010, Tinhofer, Klinghammer et al. 2011, Wheeler,Egloff et al. 2015) and 10% of squamous NSCLC (Ji, Zhao et al. 2006,Sasaki, Kawano et al. 2007), and is associated with resistance tocurrent therapeutics including the anti-EGFR antibody cetuximab (Sok,Coppelli et al. 2006, Tinhofer, Klinghammer et al. 2011). Normal tissuesdo not express this oncogenic receptor variant.

HER2-S310F is the most common mutation of HER2 expressed in humantumors, expressed by approximately 0.5% of all tumors. HER2-S310Fexpression is mutually exclusive with expression of HER2 amplification.HER2-S310F is highly oncogenic, transforming BaF3 cells (a murineinterleukin-3 (IL-3) dependent pro-B cell line) to IL-3 independence andpromoting tumor growth in vivo.

Short insertions of within Exon 20 of EGFR and HER2 are expressed bylung adenocarcinoma tumors and other tumor groups. ErbB Exon 20insertion mutants are expressed by 4-5% of lung adenocarcinoma tumors.Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH.

These ErbB Exon 20 insertion mutants are highly oncogenic, transformingBaF3 cells to IL-3 independence and promoting tumor growth in vivo.

ErbB inhibitors are a known treatment for a number of cancers. However,not every patient is responsive satisfactorily to this treatment. Thus,there is a long-felt need in the art for new therapies that are able toaddress the variable responsiveness of cancer patients to knowntherapies. The present disclosure is able to overcome some of thesedrawbacks of the standard of care, as it existed prior to thedevelopment of the compositions and methods disclosed herein.

Definitions

Unless specified otherwise defined, the following general definitionsapply to the compounds of the present disclosure according to thedescription.

The term “compound of the present disclosure,” as used herein, refers tocompounds represented by formulae I to XVI and any of the examplesdisclosed herein.

It is understood that “independently of each other” means that when agroup is occurring more than one time in any compound, its definition oneach occurrence is independent from any other occurrence.

It is understood that a dashed line (or a wave being transverse to abond) depicts the site of attachment of a residue (i.e. a partialformula).

It is also understood that a group defined as being a “covalent bond”refers to a direct linkage between its two neighbouring groups.

The following definitions regarding group Z apply to each of theembodiments cited hereinafter: the term “3 to 6-memberedheterocycloalkyl” in combination with —(NR⁴R⁵), refers to a non-aromaticor partially aromatic ring system having 3, 4, 5, or 6 ring atomsselected from C, N, O, or S, (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl. In some embodiments, a 3 to 6-memberedheterocycloalkyl is oxetanyl. In some embodiments, a 3 to 6-memberedheterocycloalkyl is tetrahydrofuranyl. In some embodiments, a 3 to6-membered heterocycloalkyl is (dioxo-)thioniorpholinyl.

A “partially aromatic” ring system is a ring system with one or moreunsaturations, which are not fully conjugated over the whole ringsystem.

The term “3 to 6-membered heteroaryl” in combination with —(NR⁶R⁷) or—(CHR⁶R⁷), refers to a (fully) aromatic ring system having 3, 4, 5, or 6ring atoms (e.g. 5 ring atoms), selected from C, N, O, or S (e.g. C, N,or O and C or N; with the number of N atoms being 0, 1, 2 or 3 and thenumber of O and S atoms each being 0, 1 or 2). Examples of “heteroaryl”include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl(pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl,thienyl, and the like. In some embodiments, “heteroaryl” is pyrrolyl,imidazolyl.

The term “3 to 9-membered heterocycloalkyl” in combination with —(NR⁶R⁷)or —(CHR⁶R⁷), refers to a non-aromatic or partially aromatic ring systemhaving 3, 4, 5, 6, 7, 8, or 9 ring atoms selected from C, N, O, or S(e.g. C, N, or O; the number of N atoms being 0, 1, 2 or 3 and thenumber of O and S atoms each being 0, 1 or 2). The term “monocycle” inconnection with a 3 to 9-membered heterocycloalkyl refers to the 3 to 9ring atoms forming a single ring. Examples of such monocycles includeoxiranyl, thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl and the like. In some embodiments,monocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, azepanyl

The term “fused bicycle” in connection with a 3 to 9-memberedheterocycloalkyl refers to the 3 to 9 ring atoms selected from C, N. O,or S, forming two or three rings (e.g. two rings) that are sharing twoadjacent atoms (i.e. one bond) and at least one ring in the fused ringsystem contains one or more heteroatoms (e.g. 1, 2 or 3 heteroatomsselected from N, O, S). Some non-limiting examples of the fusedheterobicyclyl group include 3-azabicyclo[3.1.0]hexyl,3-azabicyclo[3.3.0]octyl, 3,7-diazabicyclo[3.3.0]octyl,3-aza-7-oxabicyclo[3.3.0]octyl, 2,6-diazabicyclo[3.3.0]octyl,2,7-diazabicyclo[3.3.0]octyl, 2,8-diazabicyclo[4.3.0]nonyl,3-oxa-8-azabicyclo[4.3.0]nonyl, 2-oxa-8-azabicyclo[4.3.0]nonyl,2,8-diaza-5-oxabicyclo[4.3.0]nonyl, 4,9-diazabicyclo[4.3.0]nonyl,2,9-diazabicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl,3,7-diazabicyclo[4.3.0]nonyl, 3,9-diazabicyclo[4.3.0]nonyl,3-oxa-8-azabicyclo[4.3.0]nonyl, 3-thia-8-azabicyclo[4.3.0]nonyl, and thelike.

The term “bridged bicycle” in connection with a 3 to 9-memberedheterocycloalkyl refers to the 3 to 9 ring atoms forming a ring systemthat has a carbocyclyl or heterocyclyl, wherein two non-adjacent atomsof the ring are connected (bridged) by at least one (e.g. one or two)atoms selected from C, N, O, or S (e.g. C, N, or O), with the provisothat at least one heteroatom is present. Examples of such bridged ringsystems include bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl,bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl(e.g. bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O.

The term “spirobicycle” connection with a 3 to 9-memberedheterocycloalkyl refers to the 3 to 9 ring atoms forming a ring systemthat has two rings each of which are independently selected from acarbocyclyl or a heterocyclyl, wherein the two rings share one atom.Examples of such spiro ring systems include spiropentanyl,spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O. In some embodiments, examples includediazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl,diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl.

The term “halogen” or “hal” as used herein may be fluoro, chloro, bromoor iodo (e.g. fluoro or chloro).

The term “alkyl” as used herein refers to a fully saturated branched orunbranched hydrocarbon moiety. The term “C₁₋₄alkyl” refers to a fullysaturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl. In connection with group L, the term “straightchain or branched C₁₋₄ alkyl” refers to —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —C(CH₃)₂— or —CH₂—C(CH₃)₂—.

According to the methods of the disclosure, exemplary subjects aremammals. In some embodiments, exemplary subjects are human. Exemplarysubjects may be male or female. Exemplary subjects may be of any age(fetal, neonatal, child, adolescent, or adult) In some embodiments, thesubject is an adult. Exemplary subjects may be healthy, for example,healthy subjects of the disclosure may participate in a clinical trialin which one or more steps of the methods of the disclosure areperformed. In certain embodiments, exemplary subjects may have at leastone benign or malignant tumor. In some embodiments, exemplary subjectshave at least one form or type of cancer. Subjects of the methods of thedisclosure may be patients diagnosed with cancer, patients undergoingtreatment for cancer, potential participants in a research and/orclinical study, and/or participants selected for inclusion in orexclusion from a research and/or clinical study.

According to the methods of the disclosure, the term “mammal” refers toany mammal, including humans, domestic and farm animals, and zoo,sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs,goats, rabbits, etc. (e.g. human).

The term “prevention” or “preventing” refers to reducing or eliminatingthe onset of the symptoms or complications of a disease (e.g., cancer).In some embodiments, such prevention comprises the step of administeringa therapeutically effective amount of a compound disclosed herein (e.g.,a compound of Formula I or a pharmaceutically acceptable salt thereof)or a pharmaceutical composition disclosed herein (e.g., a pharmaceuticalcomposition containing a compound of Formula I or a pharmaceuticallyacceptable salt thereof) to a subject in need thereof (e.g., a mammal(e.g., a human).

The term “treatment” or “treating” is intended to encompass therapy andcure. In some embodiments, such treatment comprises the step ofadministering a therapeutically effective amount of a compound disclosedherein (e.g., a compound of Formula I or a pharmaceutically acceptablesalt thereof) or a pharmaceutical composition disclosed herein (e.g., apharmaceutical composition containing a compound of Formula I or apharmaceutically acceptable salt thereof) to a subject in need thereof(e.g., a mammal (e.g., a human). In some embodiments, the term“treating” or “treatment” refers to therapeutic treatment measures;wherein the object is to slow down (lessen) the targeted pathologiccondition or disorder. Those in need of treatment include those alreadywith the disorder as well as those prone to have the disorder. Forexample, when treating cancer according to a method of the disclosure, asubject or mammal is successfully “treated” for cancer if, afterreceiving a therapeutic amount of an ErbB inhibitor according to themethods of the present disclosure, the patient shows observable and/ormeasurable reduction in or absence of one or more of the following:reduction in the number of cancer cells or absence of the cancer cells;reduction in the proliferation or survival of cancer cells, and/orrelief to some extent, one or more of the symptoms associated with thespecific infection; reduced morbidity and mortality, and improvement inquality of life issues. The above parameters for assessing successfultreatment and improvement in the disease are readily measurable byroutine procedures familiar to a physician. According to the methods ofthe disclosure, subjects having a mutation of the disclosure may betreated for cancer by administering a therapeutically-effective amountof a composition of the disclosure, a Type II ErbB inhibitor, anEGFR-Viii selective agent/inhibitor or the NT-113 Type I inhibitor. Theterm “therapeutically effective amount” refers to an amount of acomposition of the disclosure, a Type 11 ErbB inhibitor, an EGFR-Viiiselective agent/inhibitor or the NT-113 Type I inhibitor effective to“treat” a disease or disorder (e.g. cancer) in a subject or mammal.

See preceding definition of “treating.”

According to the methods of the disclosure, a Type II ErbB inhibitor mayinclude a small molecule. A “small molecule” is defined herein to have amolecular weight below about 1500 Daltons.

According to the methods of the disclosure, mutations may be detected byanalyzing either nucleic acid or amino acid sequences from a subject.Nucleic acid and/or amino acid sequences may be isolated prior tosequence analysis.

The terms “nucleic acid” and “polynucleotide” are used interchangeablyherein to refer to single- or double-stranded RNA, DNA, or mixedpolymers. Polynucleotides may include genomic sequences, extra-genomicand plasmid sequences, and smaller engineered gene segments thatexpress, or may be adapted to express polypeptides.

An “isolated nucleic acid” is a nucleic acid that is substantiallyseparated from other genome DNA sequences as well as proteins orcomplexes such as ribosomes and polymerases, which naturally accompany anative sequence. The term embraces a nucleic acid sequence that has beenremoved from its naturally occurring environment, and includesrecombinant or cloned DNA isolates and chemically synthesized analoguesor analogues biologically synthesized by heterologous systems. Asubstantially pure nucleic acid includes isolated forms of the nucleicacid. This refers to the nucleic acid as originally isolated and doesnot exclude genes or sequences later added to the isolated nucleic acid.

The term “polypeptide” is used in its conventional meaning, i.e., as asequence of amino acids. The polypeptides are not limited to a specificlength of the product. Peptides, oligopeptides, and proteins areincluded within the definition of polypeptide, and such terms may beused interchangeably herein unless indicated otherwise. This term alsodoes not refer to or exclude post-expression modifications of thepolypeptide, for example, glycosylations, acetylations, phosphorylationsand the like, as well as other modifications known in the art, bothnaturally occurring and non-naturally occurring. A polypeptide may be anentire protein, or a subsequence thereof.

An “isolated polypeptide” is one that has been identified and separatedand/or recovered from a component of its natural environment. In someembodiments, the isolated polypeptide will be purified (1) to greaterthan 95% by weight of polypeptide as determined by the Lowry method(e.g. more than 99% by weight), (2) to a degree sufficient to obtain atleast 15 residues of N-terminal or internal amino acid sequence by useof a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE underreducing or non-reducing conditions using Coomassie blue or silverstain. Isolated polypeptide includes the polypeptide in situ withinrecombinant cells since at least one component of the polypeptide'snatural environment will not be present. In some embodiments, theisolated polypeptide will be prepared by at least one purification step.

A “native sequence” polynucleotide is one that has the same nucleotidesequence as a polynucleotide derived from nature. A “native sequence”polypeptide is one that has the same amino acid sequence as apolypeptide (e.g. EGFR) derived from nature (e.g., from any species).Such native sequence polynucleotides and polypeptides can be isolatedfrom nature or can be produced by recombinant or synthetic means.

A polynucleotide “variant,” as the term is used herein, is apolynucleotide that differs from a disclosed polynucleotide herein inone or more substitutions, deletions, additions and/or insertions.

A polypeptide “variant,” as the term is used herein, is a polypeptidethat differs from a disclosed polypeptide herein in one or moresubstitutions, deletions, additions and/or insertions, or inversions.Such variants may be naturally occurring, non-naturally occurring, ormay be synthetically generated.

EGFR mutations (or variants) of the disclosure may comprise one or moresubstitutions, deletions, additions and/or insertions, or inversions ofthe amino acid sequence that are alter the function of the resultantprotein. Mutations may be detected, for example, by comparison oralignment of a nucleic or amino acid sequence with a wild type sequence.

When comparing polynucleotide and polypeptide sequences, two sequencesare said to be “identical” if the sequence of nucleotides or amino acidsin the two sequences is the same when aligned for maximumcorrespondence, as described below. Comparisons between two sequencesare performed by comparing the sequences over a comparison window toidentify and compare local regions of sequence similarity. A “comparisonwindow” as used herein, refers to a segment of at least about 20contiguous positions, (e.g. 30 to about 75 or 40 to about 50), in whicha sequence may be compared to a reference sequence of the same number ofcontiguous positions after the two sequences are optimally aligned.

Optimal alignment of sequences for comparison may be conducted using theMegalign program in the Lasergene suite of bioinformatics software(DNASTAR, Inc., Madison, Wis.), using default parameters. This programembodies several alignment schemes described in the followingreferences: Dayhoff, M.O. (1978) A model of evolutionary change inproteins—Matrices for detecting distant relationships. In Dayhoff, M.O.(ed.) Atlas of Protein Sequence and Structure, National BiomedicalResearch Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; HeinJ. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.;Higgins, D. G. and Sharp, P. M. (1989) CABIOS 5:151-153; Myers, E.W. andMuller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H. A. and Sokal, R. R. (1973) Numerical Taxonomy—the Principles andPractice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.;Wilbur, W. J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA80:726-730.

Optimal alignment of sequences for comparison may be conducted by thelocal identity algorithm of Smith and Waterman (1981) Add. APL. Math2:482, by the identity alignment algorithm of Needleman and Wunsch(1970) J. Mol. Biol. 48.443, by the search for similarity methods ofPearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, bycomputerized implementations of these algorithms (GAP, BESTFIT, BLAST,FASTA, and TFASTA in the Wisconsin Genetics Software Package, GeneticsComputer Group (GCG), 575 Science Dr., Madison, Wis.), or by inspection.

One example of algorithms that are suitable for determining percentsequence identity and sequence similarity are the BLAST and BLAST 2.0algorithms, which are described in Altschul et al. (1977) Nucl. AcidsRes. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410,respectively. BLAST and BLAST 2.0 can be used, for example, with theparameters described herein, to determine percent sequence identity forthe polynucleotides and polypeptides of the present disclosure. Softwarefor performing BLAST analyses is publicly available through the NationalCenter for Biotechnology Information.

In some embodiments, cumulative scores can be calculated using, fornucleotide sequences, the parameters M (reward score for a pair ofmatching residues; always >0) and N (penalty score for mismatchingresidues; always <0). Extension of the word hits in each direction arehalted when: the cumulative alignment score falls off by the quantity Xfrom its maximum achieved value; the cumulative score goes to zero orbelow, due to the accumulation of one or more negative-scoring residuealignments; or the end of either sequence is reached. The BLASTalgorithm parameters W, T and X determine the sensitivity and speed ofthe alignment. The BLASTN program (for nucleotide sequences) uses asdefaults a wordlength (W) of 11, and expectation (E) of 10, and theBLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl.Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10,M=5, N=−4 and a comparison of both strands.

For amino acid sequences, a scoring matrix can be used to calculate thecumulative score. Extension of the word hits in each direction arehalted when: the cumulative alignment score falls off by the quantity Xfrom its maximum achieved value; the cumulative score goes to zero orbelow, due to the accumulation of one or more negative-scoring residuealignments; or the end of either sequence is reached. The BLASTalgorithm parameters W, T and X determine the sensitivity and speed ofthe alignment.

In one approach, the “percentage of sequence identity” is determined bycomparing two optimally aligned sequences over a window of comparison ofat least 20 positions, wherein the portion of the polynucleotide orpolypeptide sequence in the comparison window may comprise additions ordeletions (i.e., gaps) of 20 percent or less (e.g. 5 to 15 percent, or10 to 12 percent) as compared to the reference sequences (which does notcomprise additions or deletions) for optimal alignment of the twosequences. The percentage is calculated by determining the number ofpositions at which the identical nucleic acid bases or amino acidresidues occur in both sequences to yield the number of matchedpositions, dividing the number of matched positions by the total numberof positions in the reference sequence (i.e., the window size) andmultiplying the results by 100 to yield the percentage of sequenceidentity.

Sequences

A wild type EGFR sequence of the disclosure may comprise or consist ofthe amino acid sequence of:

(SEQ ID NO: 1, corresponding to epidermal growth factor receptor[Homo sapiens] and Genbank Accession No. CAA25240) 1mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsa cchnqcaagc 241tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361nctsisgdlh ilpvafrgds fthtppldpq eidilktvke itgflliqaw penrtdlhaf 421enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481fgtsgqktki isnrgensck atgqvchalc spegcvgpsp rdcvscrnvs rgrecvdkck 541llegeprefv enseciqchp eclpaamnit ctgrgpdnci qcahyidgph cvktcpagvm 601genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv 661algiglfmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket efkkikvlgs 721gafgtvykgl wipegekvki pvaikelrea tspkankeil deayvmasvd nphvcrllgi 781cltstvqlit qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa 841rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy 901gvtvwelmtf gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961freliiefsk mardpqrylv iqqdermhlp sptdsnfyra lmdeedmddv vaadeylipq 1021qgffsspsts rtpllsslsa tsanstvaci drnglgscpi kedsflgrys sdptgalted 1081siddtflpvp eyinqsvpkr pagsvgnpvy hnqplnpaps rdphyqdphs tavgnpeyln 1141tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpnqifkgs taenaeylrv 1201apqssefiga.

A wild type HER2 Receptor sequence of the disclosure may comprise orconsist of the amino acid sequence of:

(SEQ ID NO: 2, corresponding to receptor tyrosine-protein kinase erbB-2isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439)1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481pwdqlfrnph qallhtanrp edecvgegla chqlearghc wgpgptqcvn csqflrgqec 541veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601psgvkpdlsy npiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeea prsplapseg 1081agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv.

A wild type HER2 Receptor sequence of the disclosure may comprise orconsist of the amino acid sequence of:

(SEQ ID NO: 3, corresponding to receptor tyrosine-protein kinaseerb-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862) 1mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evfaedgtqr 301cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481chqlearghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961nedlgpaspl dstfyrslle dddmgdlvaa eeylvpqqgf fcpdpapgag gmvhhrhrss 1021strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq 1081rysedptvpl psetdgvvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201gappstfkgt ptaenpeylg ldvpv.

A wild type HER2 Receptor sequence of the disclosure may comprise orconsist of the amino acid sequence of:

(SEQ ID NO. 4, corresponding to receptor tyrosine-protein kinase erbR-2isoform c [Homo sapiens] and GenBank Accession No. NP_001276865) 1mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl ptnaslsflq 61diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala vldngdplnn ttpvtqaspg 121glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynvls tdvgsctlvc 301plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla 361flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri 421lhngaysltl qglgiswlgl rslrelgsgl alihhnthlc fvhtvpwdql frnpfqallh 481tanrpedecv geglachqlc arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541narhclpchp ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661krrqqkirky tmrrllqete lvepltpsga mpnqaqmri1 ketelrkvkv lgsgafgtvy 721kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl lgicltstvq 781lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy ledvrlvhrd laarnvlvks 841pnbvkitdfg larlldidet eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901mtfqakpydg ipareipdl1 ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa 1081kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafsp 1201afdnlyywdq dppergapps tfkgtptaen peylgldvpv.

A wild type HER2 Receptor sequence of the disclosure may comprise orconsist of the amino acid sequence of:

(SEQ ID NO: 5,corresponding to receptor tyrosine-protein kinase erbB-2 isoformd precursor [Homo sapiens] and GenBank Accession No. NP_001276866) 1melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181ltlidtnrsr achpcspmck gsrewgesse dcqsltrtvc agacarckgp lptdccheqc 241aagctgpkns dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaearasp ltsiisavvg 661illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictld vymimvkcwm 961idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021eeylvpqqgf fcpdpapgag gmvhhrhrss strnm.

A wild type HER2 Receptor sequence of the disclosure may comprise orconsist of the amino acid sequence of:

(SEQ ID NO: 6, corresponding to receptor tyrosine-protein kinase erbB-2isoform e [Homo sapiens] and GenBank Accession No. NP_001276867) 1mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421swlglrslre lgsgialihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601ths.

Based on the definitions given throughout the application the skilledperson knows which combinations are synthetically feasible andrealistic, e.g. typically combinations of groups leading to heteroatomsdirectly linked to each other are not contemplated.

Compounds of the Present Disclosure

In some aspects, the present disclosure is directed towards a compoundor pharmaceutically acceptable salts or stereoisomers thereof of formulaI

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Y² is a covalent bond, —O—, —NH—, —NCH₃—, —C≡C—;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused-, bridged- or spirobicycle or a combinationthereof, and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′,—NR′R″, wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂O—CH₃; andX is a group of formula (i)a

wherein X¹ is —O—, —CH₂—, —NH—, —S—;Ar¹ is 6 membered aryl or N-heteroaryl, which is unsubstituted orsubstituted with one or more of a group selected from hal, C₁₋₆alkyl orC₁₋₆alkoxy;Ar² is 6 membered aryl or N-heteroaryl, which is unsubstituted orsubstituted with one or more of a group selected from halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CF₃ or —OCF₃;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal (e.g. a covalent bond or —CH₂—).

In some embodiments substituent Z-L-Y₂ contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, the compound of formula I is not any of

wherein Q is

In some embodiments, An of the compound of formula (i)a orpharmaceutically acceptable salts or stereoisomers thereof is a group offormula (i)b

wherein X², X^(2′), X⁴, X^(4′) are independently of each other —N═ or—CH═; and wherein R², R^(2′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, —OCF₃, with the proviso that at least two of X²,X^(2′), X⁴, X^(4′) are —CH═.

It is understood that R², R^(2′) can only be bound to X-groups being—CH═.

In some embodiments, 2, 3 or all of X², X^(2′), X⁴, X^(4′) are —CH═ andthus Ar₁ of formula (i)b is selected from phenyl, pyridine, pyridazine,pyrimidine and pyrazine ring system.

In some embodiments, Ari of formula (i)b is a phenyl group a (e.g. a1)

In some embodiments, Ar₁ of formula (i)b is one of groups b or c (e.g.,b1 or c1), wherein the pyridine is linked to the amino group in ortho-or meta-position to the ring nitrogen

In some embodiments, Ar₁ of formula (i)b is one of groups d or e,wherein the pyrimidine is linked to the amino group in ortho- ormeta-position to the ring nitrogen

In some embodiments, Ar₁ of formula (i)b is a pyridazine group f. Insome embodiments, Ar₁ of formula (i)b is the following pyrazine group g.

In some embodiments of Art, both X⁴ and X^(4′) are —CH═.

In some embodiments, Ar₁ is

-   -   ring a (or a1) wherein X², X^(2′), X⁴ and X^(4′) are —CH═; or    -   ring b (or b1) wherein X² is —N═ and X^(2′), X⁴, X^(4′) are        —CH═; or    -   ring c (or c1) wherein X^(2′) is —N═ and X², X⁴, X^(4′) are        —CH═; or    -   ring f wherein X², X^(2′) are —N═ and X⁴, X^(4′) are —CH═.

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl (e.g. methyl), halogen (e.g. Cl or F).

In some embodiments, Ar₂ of the compound of formula (i)a orpharmaceutically acceptable salts or stereoisomers thereof is a group offormula (i)c

wherein X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other —N═,—CH═; and R³, R^(3′) are independently of each other H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃, with the proviso that at least two of X³, X^(3′), X⁵,X^(5′), X⁶ are —CH═.

In some embodiments, R³, R^(3′) can only be bound to X-groups being—CH═.

In some embodiments, 2, 3 or all of X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═and thus Ar₂ of formula (i)c is selected from phenyl, pyridine,pyridazine, pyrimidine and pyrazine.

In some embodiments, Ar₂ of formula (i)c is a phenyl group a′ (e.g. a′1)

In some embodiments, Ar₂ of formula (i)c is one of groups b′ or c′ or d′(e.g. b′1 or c′1 or d′ 1), wherein the pyridine is linked in ortho- ormeta- or para-position to the ring nitrogen

In some embodiments, Ar₂ of formula (i)c is one of groups e′ or f′ (e.g.e′1 or f′1), wherein the pyrimidine is linked in ortho- or meta-positionto the ring nitrogens

In some embodiments, Ar₂ of formula (i)c is group g′ (e.g. g′1). In someembodiments, Ar₂ of formula (i)c is a pyrazine group h′ (e.g. h′1)

In some embodiments, Ar₂ of formula (i)c is group i′ (e.g. i′1). In someembodiments, Ar₂ of formula (i)c is a pyrazine group k′ (e.g. k′1).

In some embodiments of Ar₂, both X⁵ and X^(5′) are —CH═.

In some embodiments, Ar₂ is

-   -   ring a′ wherein X³, X^(3′), X⁵, X^(5′) and X⁶ are —CH═; or    -   ring b′ wherein X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═; or    -   ring c′ wherein X^(3′) is —N═ and X³, X⁵, X^(6′), X⁶ are —CH═;        or    -   ring d′ wherein X⁶ is —N═ and X³, X^(3′), X⁵, X^(5′) are —CH═;        or    -   ring g′ wherein X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═;        or    -   ring i′ wherein X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═;        or    -   ring k′ wherein X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) 0 are        —CH═.

In some embodiments of Ar₂, both X^(3′) and X⁶ are —CH═.

In some embodiments, Ar₂ is

-   -   ring e′ wherein X³, X⁵ are —N═ and X^(3′), X^(5′), X⁶ are —CH═;        or    -   ring h′ wherein X³, X^(5′) are —N═ and X^(3′), X⁵, X⁶ are —CH.

In some embodiments of Ar₂, both X³ and X⁶ are —CH═.

In some embodiments, Ar₂ is

-   -   ring f wherein X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are —CH═

The present disclosure includes all possible combinations of group (i)bwith group (i)c linked by the linker -X¹-L¹-, e.g., a combination of awith either group a′-k′ (aa′, ab′, ac′, ad′, ae′, af′, ag′, ah′, ai′,ak′); a combination of b with either group a′-k′ (ba′, bb′, bc′, bd′,be′, bf′, bg′, bh′, bi′, bk′); a combination of c with either groupa′-k′ (ca′, cb′, cc′, cd′, ce′, cf′, cg′, ch′, ci′, ck′); a combinationof d with either group a′-k′ (da′, db′, dc′, dd′, de′, df′, dg′, dh′,di′, dk′); a combination of e with either group a′-i′ (ea′, eb′, ec′,ed′, ee′, ef′, eg′, eh′, ei′, ek′); a combination of f with either groupa′-k′ (fa′, fb′, fc′, fd′, fe′, ff′, fg′, fh′, fi′, fk′); or g witheither group a′-k′ (ga′, gb′, gc′, gd′, ge′, gf′, gg′, gh′, gi′, gk′).

In some embodiments, the ring combinations include

-   -   aa′ or ab′ or ac′ or ad′    -   ae′ or ag′ or ah′ or ai′    -   bb′ or cb′.

In some embodiments of the compound of formula (i)a are directed togroups X¹ and L¹, which form together the linker between Ar₁ and Ar₂. Insome embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. In someembodiments, X¹ is —NH—. In some embodiments, X¹ is —S—.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is—CH₂—, —CH(CH₃)—, or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂—,—CH₂—CH(CH₃)—, or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- for each of thecombinations of (i)b and (i)c include —O—, —CH₂—, —O—CH₂—, —NH—CH₂—,—S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—, —NH—CH(CH₃)—,—S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-, —S—CH(hal)-(e.g., —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)- (e.g., —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, or —CH₂—CH₂—)).

In some embodiments, a group of formula (i)a is selected from thecombinations

(i) a-O-a′, a-O—CH₂-a′, a-O—CH(CH₃)-a′, a-O—CH(hal)-a′, and a-NH-a′,a-NH—CH₂-a′, a-NH—CH(CH₃)-a′, a-NH—CH(hal)-a′,(ii) a-O-b′, a-O—CH₂-b′, a-O—CH(CH₃)-b′, a-O—CH(hal)-b′, and a-NH-b′,a-NH—CH₂-b′, a-NH—CH(CH₃)-b′, a-NH—CH(hal)-b′,(iii) a-O-c′, a-O—CH₂-c′, a-O—CH(CH₃)-c′, a-O—CH(hal)-c′, and a-NH-c′,a-NH—CH₂-c′, a-NH—CH(CH₃)-c′, a-NH—CH(hal)-c′,(iv) a-O-d′, a-O—CH₂-d′, a-O—CH(CH₃)-d′, a-O—CH(hal)-d′, and a-NH-d′,a-NH—CH₂-d′, a-NH—CH(CH₃)-d′, a-NH—CH(hal)-d′,(v) a-O-e′, a-O—CH₂-e′, a-O—CH(CH₃)-e′, a-O—CH(hal)-e′, and a-NH-e′,a-NH—CH₂-e′, a-NH—CH(CH₃)-e′, a-NH—CH(hal)-e′, (vi) a-O-g′, a-O—CH₂-g′,a-O—CH(CH₃)-g′, a-O—CH(hal)-g′, and a-NH-g′, a-NH—CH₂-g′,a-NH—CH(CH₃)-g′, a-NH—CH(hal)-g′,(vii) a-O-h′, a-O—CH₂-h′, a-O—CH(CH₃)-h′, a-O—CH(hal)-h′, and a-NH-h′,a-NH—CH₂-h′, a-NH—CH(CH₃)-h′, a-NH—CH(hal)-h′,(viii) a-O-i′, a-O—CH₂-i′, a-O—CH(CH₃)-i′, a-O—CH(hal)-i′, and a-NH-i′,a-NH—CH₂-i′, a-NH—CH(CH₃)-i′, a-NH—CH(hal)-i′,(ix) b-O-b′, b-O—CH₂-b′, b-O—CH(CH₃)-b′, b-O—CH(hal)-b′, and b-NH-b′,b-NH—CH₂-b′, b-NH—CH(CH₃)-b′, b-NH—CH(hal)-b′,(x) c-O-b′, c-O—CH₂-b′, c-O—CH(CH₃)-b′, c-O—CH(hal)-b′, and c-NH-b′,c-NH—CH₂-b′, c-NH—CH(CH₃)-b′, c-NH—CH(hal)-b′.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, or tetrahydrofuryl.

Group Z is as defined above. In some embodiments of a compound offormula I, a 3 to 6-membered heterocycloalkyl (in combination with—(NR⁴R⁵)) refers to a non-aromatic or partially aromatic ring systemhaving 3, 4, 5, or 6 ring atoms selected from C, N, O, and/or S, (e.g.,C, N, and/or O). In some embodiments, the number of N atoms is 0, 1, or2. In some embodiments, the number of O and S atoms each is 0, 1, or 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula I, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g., 3,4, or 5 ring atoms), selected from C, N, O, and/or S, (e.g. C, N, and/orO, and C or N). In some embodiments, the number of N atoms is 0, 1, 2 or3. In some embodiments, the number of O and S atoms each is 0, 1 or 2.Examples of “heteroaryl” include furyl, imidazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, thiazolyl, thienyl, and the like. Examples of“heteroaryl” include pyrrolyl, imidazolyl.

In some embodiments of a compound of formula I, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, and/or S (e g, C, N, and/or O). In someembodiments, the number of N atoms is 0, 1, 2 or 3. In some embodiments,the number of O and S atoms each is 0, 1 or 2. Examples of a 3 to9-membered heterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷))include monocycles such as oxiranyl, thiaranyl, aziradinyl, oxetanyl,thiatanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl,1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl 1,4-dithianyl, 1,3-dioxane,1,3-dithianyl, piperazinyl, thiomorpholinyl, dioxothiomorpholinyl,piperidinyl, morpholinyl, oxepanyl, thiepanyl, azepanyl, diazepanyl,oxazepanyl (e.g. azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, azepanyl); fused ring systems, such as3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O; spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl, having one or two heteroatomsselected from N and O, (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl)).

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₄ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl. Insuch embodiments, Z includes at least one nitrogen atom.

In some embodiments of a compound of formula I, the following variationsof group R¹ are included, which apply to each of the embodiments citedabove. In some embodiments, R¹ is —CR_(b)═CHR_(a), wherein R^(a), R^(b)are independently of each other H, hal, —CH₂—O—CH₃. In some embodiments,R¹ is —CH═CH₂. In some embodiments, R¹ is —CH═CH-hal or —C(hal)=CH₂. Insome embodiments, R¹ is —CH═CH—CH₂—O—CH₃. In some embodiments, R¹ is—C≡CH or —C≡C—CH₃.

In some embodiments, Y² is covalent bond. In some embodiments, Y² is—O—. In some embodiments, Y² is —NH— or NCH₃—. In some embodiments, Y²is —C≡C—.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —C(CH₃)₂—, or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4 (e.g.,0, 1, or 2). In some embodiments, m2 is 0 and m1 is 0 or 1 or 2. In someembodiments, m1 and m2 are 1 or m1 and m2 are 2.

In some aspects, the present disclosure is directed towards a compoundor pharmaceutically acceptable salts or stereoisomers thereof of formulaI

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Y² is a covalent bond, —O—, —NH—, —NCH₃—, —C≡C—;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃; andX is a group of formula (ii)a,

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal.

In some embodiments substituent Z-L-Y₂ contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y₂ is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments of a compound of formula I, the following variationsof group R¹ are included, which apply to each of the embodiments citedabove. In some embodiments, R¹ is —CR_(b)═CHR_(a), wherein R^(a), R^(b)are independently of each other H, hal, —CH₂—O—CH₃. In some embodiments,R¹ is —CH═CH₂. In some embodiments, R¹ is —CH═CH-hal or —C(hal)=CH₂. Insome embodiments, R¹ is —CH═CH—CH₂—O—CH₃. In some embodiments, R¹ is—C≡CH or —C≡C—CH₃.

Each of the following definitions equally applies to a compound offormula I.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- for (ii)a include —O—,—CH₂—, —O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-,—NH—CH(hal)-, —S—CH(hal)- (e.g., —O—, —CH₂—, —O—CH₂—, —NH—CH₂—,—CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)- (e.g.,—O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—)).

In some embodiments, -X¹-L¹- is —O—. In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, group X has the following formula (ii)b,(e.g. (ii)b-1 or (ii)b-2):

wherein X², X^(2′) and X³, X³⁺, X⁵, X⁵⁺, X⁶ are independently of eachother —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, group X has the following formula (ii)d-1, (ii)d-2,(ii)d-3, (ii)d-4, (ii)d-5

wherein X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═or —CH═; and R², R^(2′), R³, R^(3′), are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, group X has the following formula (ii)e-1, (ii)e-2,(ii)e-3, (ii)e-4, (ii)e-5 or (ii)e-6

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X^(6′) are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—. In some embodiments, group X has the following formula (ii)c(e.g. (ii)c-1 or (ii)c-2):

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, or hal (e.g., H, —CH₃, F, or Cl). In some embodiments, R³and R^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, or—OCF₃.

In some embodiments, group X has the following formula (ii)f-1, (ii)f-2,(ii)f-3, (ii)f-4, (ii)f-5 or (ii)f-6

wherein X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═or —CH═, and R², R^(2′), R³, R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, group X has the following formula (ii)g-1, (ii)g-2,(ii)g-3, (ii)g-4, (ii)g-5 or (ii)g-6

whereinX², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, or hal (e.g., H, —CH₃, F, or Cl). In some embodiments, R³and R^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, or—OCF₃.

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃. In some embodiments,R^(3′) is H, hal or C₁₋₆ alkyl (e.g., H, hal or —CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments of a compound of the present disclosure, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′) are is H, C₁₋₆ alkyl, hal, —CF₃,—OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula I group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of the present disclosure, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of formula I, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl), R³, R^(3′) S are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃,and n is 0 or 1.

In some embodiments of a compound of formula I, group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula I group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of formula I group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1,

In some embodiments, R⁴ and R⁵ are independently of each other H, C1-4alkyl, cyclopropyl, tetrahydrofuryl.

In some embodiments of a compound of formula I, a 3 to 6-memberedheterocycloalkyl (in combination with —(NR⁴R⁵)) refers to anon-aromatic, or partially aromatic ring system having 3, 4, 5, or 6ring atoms selected from C, N, O, of S (e C, N, or O), the number of Natoms being 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, (e.g. oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl).

In some embodiments of a compound of formula I, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms, (e.g. 5ring atoms), selected from C, N, O, or S (e.g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like. In some embodiments, “heteroaryl” include pyrrolyl,imidazolyl. Preferably, the aromatic ring system is a nitrogencontaining heteroaryl.

In some embodiments of a compound of formula I, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, or S, (e g. C, N, or O), the number of N atomsbeing 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.Examples of a 3 to 9-membered heterocycloalkyl (in combination with—(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl, thiaranyl,aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl) fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O; spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O, (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl). Preferably, the 3 to 9-memberedheterocycloalkyl contains at least one nitrogen atom.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, Y² is covalent bond. In some embodiments, Y² is—O—. In some embodiments, Y² is —NH—, NCH₃—. In some embodiments, Y² is—C≡C—.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl, (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, 4, (e.g. 0 or1 or 2). In some embodiments, m2 is 0 and m1 is 0 or 1 or 2. In someembodiments, m1 and m2 are 1 or m1 and m2 are 2.

In some embodiments, the compound of formula I is not any of

wherein Q is

In some embodiments, the present disclosure is directed towards acompound or pharmaceutically acceptable salts or stereoisomers thereofof formula II or III

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Y² is a covalent bond, —O—, —NH—, —NCH₃—, —C≡C—;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl; R^(a),R^(b) are independently of each other H, hal, or —CH₂—O—CH₃, (e.g. H),and R_(e) is H or methyl; andX is a group of formula (ii)a

wherein X¹ is —O—, —CH₂—, —NH—, —S—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═, —CH═;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;

In some embodiments substituent Z-L-Y₂ contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if Y² is notN(H) or (NMe) or L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

-   -   In some embodiments, X¹ is —O—. In some embodiments, X¹ is        —CH₂—. In some embodiments, X¹ is —NH—. In some embodiments, X¹        is —S—. In some embodiments, L¹ is a covalent bond. In some        embodiments, L¹ is —CH₂— or —CH(CH₃)— or —CH(hal)-. In some        embodiments, L¹ is —CH₂—CH₂— or —CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- for (ii)a include —O—,—CH₂—, —O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-,—NH—CH(hal)-, —S—CH(hal)-, (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—,—CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and—O—, —CH₂—, —O—CH₂—, —NH—CH₂—, or —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, group X has the following formula (ii)b(e.g. (ii)b-1 or (ii)b-2):

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X⁶ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X^(5′), X⁶ are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X⁶ are —N═ and X^(3′),X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, group X has the following formula (ii)d-1, (ii)d-2,(ii)d-3, (ii)d-4, (ii)d-5 or (ii)d-6

wherein X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═or —CH═; and R², R^(2′), R³, R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0 or 1.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, group X has the following formula (ii)e-1, (ii)e-2,(ii)e-3, (ii)e-4, (ii)e-5 or (ii)e-6

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is-N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═or X³ is —N═ and X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—. In some embodiments, group X has the following formula (ii)c,(e.g. (ii)c-1 or (ii)c-2):

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵,X⁶ are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e.a pyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

R² and R^(2′) are independently of each other H, C₁₋₆ alkyl, hal (e.g.H, —CH₃, F, Cl). In some embodiments, R³ and R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, group X has the following formula (ii)f-1, (ii)f-2,(ii)f-3, (ii)f-4, (ii)f-5 or (ii)f-6

wherein X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═or —CH═; and R², R^(2′), R³, R^(3′), are independently of each other H,C₁₋₆alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, group X has the following formula formula (ii)g-1,(ii)g-2, (ii)g-3, (ii)g-4, (ii)g-5 or (ii)g-6

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, the following combinations of R³ and R^(3′) and R²and R^(2′) are included. In some embodiments, R³ and R^(3′) are H. Insome embodiments, R³ and R^(3′) are hal. In some embodiments, R³ is hal,—CF₃, or —OCF₃ and R^(3′) is H. In some embodiments, R³ is H and R^(3′)is hal, or C₁₋₆ alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments of a compound of formula II or III, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are is H, C₁₋₆ alkyl, hal, —CF₃,—OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1.

In some embodiments of a compound of formula II or III, group X is

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl.

In some embodiments of a compound of formula II or III, a 3 to6-membered heterocycloalkyl (in combination with —(NR⁴R⁵)) refers to anon-aromatic or partially aromatic ring system having 3, 4, 5, or 6 ringatoms selected from C, N, O, or S (e.g. C, N, or O), the number of Natoms being 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula II or III, a 3 to6-membered heteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refersto a (fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g.5 ring atoms), selected from C, N, O, or S (e g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like.

In some embodiments, “heteroaryl” include pyrrolyl, imidazolyl.Preferably, the aromatic ring system is a nitrogen containingheteroaryl.

In some embodiments of a compound of formula II or III, a 3 to9-membered heterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷))refers to a non-aromatic or partially aromatic ring system having 3 to 9ring atoms selected from C, N, O, or S (e.g. C, N, or O), the number ofN atoms being 0, 1, 2 or 3 and the number of O and S atoms each being 0,1 or 2. Examples of a 3 to 9-membered heterocycloalkyl (in combinationwith —(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl), fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O; spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl). Preferably, the 3 to 9-memberedheterocycloalkyl contains at least one nitrogen atom.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, Y² is covalent bond. In some embodiments, Y² is—O—. In some embodiments, Y² is —NH— or NCH₃—. In some embodiments, Y²is —C≡C—.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, 4 (e.g. 0 or1 or 2). In some embodiments, m2 is 0 and m1 is 0 or 1 or 2. In someembodiments, m1 and m2 are 1 or m1 and m2 are 2.

In some embodiments, the compound of formula II is not any of

wherein

In some embodiments, the present disclosure is directed towards acompound or pharmaceutically acceptable salts or stereoisomers thereofof formula I above wherein Y² is covalent bond, having the followingformula IV

wherein X¹ is —O—, —CH₂—, —NH—; X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal;R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃, wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are is —CH═ or X⁶ is —N═and X³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(3′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

The following embodiments apply for the compounds of formula IV.

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring).

In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═.

In some embodiments, L is a covalent bond.

In some embodiments, L is

-   -   wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4.        R² and R^(2′) are independently of each other H, C₁₋₆alkyl, hal        (e.g. H, —CH₃, F, Cl).

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)-, (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—,—O—CH(CH₃)—, —CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—,—CH₂—, —O—CH₂—, —NH—CH₂—, or —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—. In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, compound IV has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula IV.

In some embodiments of a compound of formula IV, IV-1, IV-1a or IV-1bsubstituent Z-L contains at least one nitrogen atom. Thus, the3-6-membered heteroaryl or 3-9-membered heterocycloalkyl formed by R₆and R₇ of (CHR₆R₇) includes a nitrogen atom if L does not contain anitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring).

In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═.

In some embodiments, L is a covalent bond.

In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4.

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, a compound of formula IV has one of the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹ are as definedabove for a compound of formula IV.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula IV has the following formulaIVe-1, IVe-2, IVe-3, IVe-4, IVe-5 or IVe-6

wherein W is

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═, and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵,X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—.

In some embodiments, a compound of formula IV has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula IV.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring).

In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, a compound of formula IV has one of the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹ are as definedabove for a compound of formula IV.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R⁶ and R⁷ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula IV has the following formula

wherein W is

X², X^(2′), X³, X^(3′),X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═, and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X⁶ are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring).

In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═.

In some embodiments, R² and R^(2′) are independently of each other (i.e.H, hal or C₁₋₆ alkyl and H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g., H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal, or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, a compound of formula IV has the following formula

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula IV. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)h-a-1 orIV-(ii)i-a-1, substituent Z-L contains at least one nitrogen atom. Thus,the 3-6-membered heteroaryl or 3-9-membered heterocycloalkyl formed byR₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does not contain anitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula IV has the following formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments of a compound of formula IV-(ii)h-c-1, IV-(ii)h-b-1or IV-(ii)h-d-1, substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R⁶ and R⁷ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.In some embodiments, a compound of formula IV has the following formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula IV. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)i-c-1, IV-(ii)i-b-1or IV-(ii)i-d-1, 210 substituent Z-L contains at least one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula IV has the following formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula IV. In some embodiments, n is 0.In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)h-e-1, IV-(ii)h-f-1,IV-(ii)h-g-1, IV-(ii)h-h-1, IV-(ii)h-i-1 or IV-(ii)h-j-1, substituentZ-L contains at least one nitrogen atom. Thus, the 3-6-memberedheteroaryl or 3-9-membered heterocycloalkyl formed by R₆ and R₇ of(CHR₆R₇) includes a nitrogen atom if L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula IV has the following formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula IV. In some embodiments, n is 0.In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)i-e-1, IV-(ii)i-f-1,IV-(ii)i-g-1, IV-(ii)i-h-1, IV-(ii)i-i-1 or IV-(ii)i-j-1, substituentZ-L contains at least one nitrogen atom. Thus, the 3-6-memberedheteroaryl or 3-9-membered heterocycloalkyl formed by R₆ and R₇ of(CHR₆R₇) includes a nitrogen atom if L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula IV has the following formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula IV. In some embodiments, n is 0.In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)h-k-1, IV-(ii)h-1-1,IV-(ii)h-m-1, IV-(ii)h-n-1, IV-(ii)h-o-1 or IV-(ii)h-p-1, substituentZ-L contains at least one nitrogen atom. Thus, the 3-6-memberedheteroaryl or 3-9-membered heterocycloalkyl formed by R₆ and R₇ of(CHR₆R₇) includes a nitrogen atom if L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula IV has the following formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula IV. In some embodiments, n is 0.In some embodiments, n is 1.

In some embodiments of a compound of formula IV-(ii)i-k-1, IV-(ii)i-1-1,IV-(ii)i-m-1, IV-(ii)i-n-1, IV-(ii)i-o-1 or IV-(ii)i-p-1 substituent Z-Lcontains at least one nitrogen atom. Thus, the 3-6-membered heteroarylor 3-9-membered heterocycloalkyl formed by R₆ and R₇ of (CHR₆R₇)includes a nitrogen atom if L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, or tetrahydrofuryl.

In some embodiments of a compound of formula IV, a 3 to 6-memberedheterocycloalkyl (in combination with —(NR⁴R⁵)) refers to a non-aromaticor partially aromatic ring system having 3, 4, 5, or 6 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula IV, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g. 5ring atoms), selected from C, N, O, or S (e g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like. In some embodiments, examples of “heteroaryl” includepyrrolyl, imidazolyl. Preferably, the aromatic ring system is a nitrogencontaining heteroaryl.

In some embodiments of a compound of formula IV, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, or S (e g. C, N, or O), the number of N atomsbeing 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.Examples of a 3 to 9-membered heterocycloalkyl (in combination with—(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl, thiaranyl,aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl); fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O, spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl). Preferably, the 3 to 9-memberedheterocycloalkyl contains at least one nitrogen atom.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, ring systems for the compounds of formula IVinclude

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl, X⁷is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, compound of formula IV has the formula V or VI

wherein X¹ is —O—, —CH₂—, —NH—; X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal.R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁶R⁷)— or —(CHR⁶R⁷)—, wherein R⁶ and R⁷ form together with theatom to which they are attached to 3 to 6-membered heteroaryl or 3 to9-membered heterocycloalkyl, wherein the 3 to 9-memberedheterocycloalkyl is a monocycle or a fused, bridged or spirobicycle or acombination thereof, and is unsubstituted or substituted with C₁₋₄alkyl, hal, —OR′, —NR′R″, wherein R′, R″ are independently of each otherH or —C₁₋₄ alkyl,R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H), and R_(e) is H or methyl.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X² is —CH═ or X^(2′) is —N═ and X² is—CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X^(3′), X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring). In some embodiments ofthe compounds of formula V or VI X², X^(2′) are —CH═.

In some embodiments of the compounds of formula V or VI X³ is —N═ andX^(3′), X⁵, X^(5′), X⁶ are —CH═.

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments of compounds of formula V or VI, R² and R^(2′) are Hand R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R²and R^(2′) are hal and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′)is H, hal; or R² is hal and R^(2′) is H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃); X⁶ is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁷ is —O—, —NH— or —N(CH₃)—,—SO₂.

In some embodiments, —(CR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl, (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1 or 2.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, the linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)-, (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—,—O—CH(CH₃)—, —CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)-, and —O—,—CH₂—, —O—CH₂—, —NH—CH₂—, or —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—. In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, -X¹-L¹- is —NH—. In some embodiments,-X¹-L¹- is —NH—CH₂—. In some embodiments, a compound of formula V or VIhas the formula V-1, VI-1, or V-2, VI-2

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═, —CH═;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁶R⁷)— or —(CHR⁶R⁷)—, wherein R⁶ and R⁷ form together with theatom to which they are attached to 3 to 6-membered heteroaryl or 3 to9-membered heterocycloalkyl, wherein the 3 to 9-memberedheterocycloalkyl is a monocycle or a fused, bridged or spirobicycle or acombination thereof, and is unsubstituted or substituted with C₁₋₄alkyl, hal, —OR′, —NR′R″, wherein R′, R″ are independently of each otherH or —C₁₋₄alkyl,R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H); R_(e) is H or methyl and n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, a compound of formula V-1, VI-1 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(e) _(a), R^(b),R^(e) are as defined above for a compound of formula V and VI (or V-1,VI-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula V-1, VI-1 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring). In some embodiments, acompound of formula V-2, VI-2 has one of the following formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(e) _(a), R^(b),R^(e) are as defined above for a compound of formula V and VI (or V-2,VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula V-2, VI-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H_(e) C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1,

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X² is—CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments substituent Z-L contains at least one nitrogen atom,Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other (e.g.H, hal or C₁₋₆ alkyl and H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ and R³ isH. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, a compound of formula V-1, VI-1, or V-2, VI-2 hasthe formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula V and VI (or V-1, VI-1, or V-2, VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-1, VI-1 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula V and VI (or V-1, VI-1, or V-2, VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-1 has the formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1, or V-2, VI-2).

In some embodiments, R² is halogen, such as C1.

In some embodiments, R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula V-2, VI-2 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal,(e.g. H, —CH₃, F, Cl); R³, R^(3′), are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula V and VI (or V-2, VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-1, VI-1 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-2, VI-2 has the formulas

wherein R² is C₁₋₆ alkyl, hal (e.g. (H, —CH₃, F, Cl); R³, R^(3′) are isH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-2, VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-1, VI-1 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula V-2, VI-2 has the formulas

wherein R² is H, C₁₋₆alkyl, hal (e.g. H, —CH, F, Cl) R³, R^(3′) are isH, C₁₋₆alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a), R^(b),R^(e) are as defined above for a compound of formula V and VI (or V-2,VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, group Z is defined as specified above. In someembodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of eachother H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z isselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂, and

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z isselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), X⁶ is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁵ is —O—, —NH— or —N(CH₃)—,—SO₂.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl, (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, 4, (e.g. 0, 1or 2). In some embodiments, m2 is 0 and m1 is 0 or 1 or 2. In someembodiments, m1 and m2 are 1 or m1 and m2 are 2.

In some embodiments, the present disclosure is directed towards acompound or pharmaceutically acceptable salts or stereoisomers thereofof formula I above wherein Y² is —O—, having the following formula VII

wherein X¹ is —O—, —CH₂—, —NH—, —S—;X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R areindependently of each other H, hal, —CH₂—O—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are is —CH═ or X⁶ is —N═and X³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X^(3′), X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl).

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, or —CH₂—CH₂—).

In some embodiments, the compound of formula VII is not any of

wherein Q is

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, compound VII has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula VII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, compound of formula VII has the following formulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹ are as definedabove for a compound of formula VII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁵ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula VII has the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, the compound of formula VII-1 is not any of

wherein Q is

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—. In some embodiments, compound VII has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula VII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵,X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R³ is H.

In some embodiments, a compound of formula VII has one of the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹ are as definedabove for a compound of formula VII.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula VII has the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X⁶ —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

R² and R^(2′) are independently of each other H, hal or C₁₋₆ alkyl (e.g.H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, a compound of formula VII has the following formula

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0or 1; and Z, L, R¹ are as defined above for a compound of formula VII.In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula VII. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R² is H, C—R alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) are H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula VII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula VII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl), R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula VII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula VII. In some embodiments, n is0. In some embodiments, n is 1. In some embodiments substituent Z-Lcontains at least one nitrogen atom. Thus, the 3-6-membered heteroarylor 3-9-membered heterocycloalkyl formed by R₆ and R₇ of (CHR₆R₇)includes a nitrogen atom if L does not contain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl.

In some embodiments of a compound of formula VII, a 3 to 6-memberedheterocycloalkyl (in combination with —(NR⁴R⁵)) refers to a non-aromaticor partially aromatic ring system having 3, 4, 5, or 6 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula VII, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g. 5ring atoms), selected from C, N, O, or S, (e.g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like. In some embodiments, examples of “heteroaryl” includepyrrolyl, imidazolyl. Preferably, the aromatic ring system is a nitrogencontaining heteroaryl.

In some embodiments of a compound of formula VII, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, or S (e g. C, N, or O), the number of N atomsbeing 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.Examples of a 3 to 9-membered heterocycloalkyl (in combination with—(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl, thiaranyl,aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl); fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O; spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O, (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl) Preferably, the 3 to 9-memberedheterocycloalkyl contains at least one nitrogen atom.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, the compound of formula VII has the formula VIII orIX

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;

R^(a), R^(b) are independently of each other H, hal, or —CH₂O—CH₃, (e.g.H), and R_(e) is H or methyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R⁶ and R⁷ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl (e.g. methyl).

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1 or 2.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, or —CH₂—CH₂—)

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, -X¹-L¹- is —NH—. In some embodiments,-X¹-L¹- is —NH—CH₂—.

In some embodiments, the compound of formula VIII is not any of

wherein Q is

In some embodiments, the compound of formula VIII or IX has the formulaVIII-1, VIII-2 or IX-1, IX-2

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═, —CH═;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;

R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H), and R is H or methyl, and n is 0 or 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring). R² and R^(2′) areindependently of each other H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). Insome embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal, or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, a compound of formula VIII-1, IX-1 has one of thefollowing formulas

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(a), R^(b), R^(e) and R¹are as defined above for a compound of formula VIII or IX (or VIII-1,IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁵ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula VIII-1, IX-1 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1 and Z, L, R^(a),R^(b), R^(e) and R¹ are as defined above for a compound of formula VIIIor IX (or VIII-1, IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X³,X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X^(5′) are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, a compound of formula VIII-2, IX-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(e), R^(b), R^(e)are as defined above for a compound of formula V and VI (or V-2, VI-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula VIII-2, IX-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1 and Z, L, R^(a),R^(b), R^(e) and R¹ are as defined above for a compound of formula VIIIor IX (or VIII-1, IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other H,hal or C₁₋₆ alkyl (e.g. H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, orC₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, a compound of formula VIII-1, VIII-2 or IX-1, IX-2has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula VIII and IX (or VIII-1, IX-1 or VIII-2, IX-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula VIII-1, IX-1 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula VIII and IX (or VIII-1, IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula IX-1 has the formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1, or V-2, VI-2).

In some embodiments, a compound of formula VIII-2, IX-2 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula VIII or IX (or VIII-2, IX-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula VIII-1, IX-1 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula VIII and IX(or VIII-1, IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula VIII-2, IX-2 has the formulas

wherein R² is H, C₁₋₆alkyl, hal (e.g. H, —CH₃, F, Cl) R³, R— are H,C₁₋₆alkyl, hal, —CF₃—OCF₃; and n is 0 or 1; and Z, L, R^(a), R^(b),R^(e) are as defined above for a compound of formula VIII or IX (orVIII-2, IX-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula VIII-1, IX-1 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula VIII and IX(or VIII-1, IX-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula VIII-2, IX-2 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula VIII and IX(or VIII-2, IX-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, group Z is defined as specified above. In someembodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of eachother H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —NR), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z areselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂, and

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —C(CH₃)₂— or—CH₂—C(CH₃)₂— and —(CH₂)₂— or —(CH₂)₃— or —CH₂—C(CH₃)₂—). In someembodiments, L is

wherein m1, m2 are independently of each other 0, 1, 2, 3, 4 (e.g. 0 or1 or 2). In some embodiments, m2 is 0 and m1 is 0 or 1 or 2. In someembodiments, m1 and m2 are 1 or m1 and m2 are 2.

In some embodiments, the compound of formula VIII-1 is not any of

wherein Q is

In some embodiments, the present disclosure is directed towards acompound or pharmaceutically acceptable salts or stereoisomers thereofof formula I above wherein Y² is —NR′″—, having the following formula X

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a), R^(b) areindependently of each other H, hal, —CH₂—O—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;

R′″ is H or —CH₃;

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or XV is —N═ and X³, X⁵, X^(5′), X⁶ are is —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments the compounds of formula X, groups X², X^(2′) are—CH═ (i.e. a phenyl ring). In some embodiments of the compounds offormula X, groups X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring) or X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridinering).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, or hal (e.g., H, —CH₃, F, or Cl).

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring) or X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridinering).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is—CH₂— or —CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—.

In some embodiments, compound of formula X has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹, R′″ are as defined above for a compound of formula X.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments of the compounds of formula X, groups X², X^(2′) are—CH═ (i.e. a phenyl ring).

In some embodiments of the compounds of formula X, groups X³, X^(3′),X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring) or X³ is —N═ and X^(3′),X⁵, X^(5′), X⁶ are —CH═(a pyridine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, compound of formula X has the following formulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ are asdefined above for a compound of formula X.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula X has the following formulas

wherein W is

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵,X⁶ are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e.a pyrimidine ring). In some embodiments, both X³, X^(5′), are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring) orX³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—. In some embodiments, compound X has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2,3; andZ, L, R¹, R′″ are as defined above for a compound of formula X.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, RI both X², X^(2′)are —N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring) or X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridinering). In some embodiments, L is a covalent bond, straight chain orbranched C₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, a compound of formula X has one of the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ are asdefined above for a compound of formula X.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula X has the following formulas

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1 and Z, L, R¹, R′″ are asdefined above for a compound of formula X.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X^(6′) are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring) orX³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, R² and R^(2′) are independently of each other (e.g.H, hal or C₁₋₆ alkyl and H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ and R³ isH. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆ alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments of a compound of formula X has the following formula

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0or 1; and Z, L, R¹, R′″ are as defined above for a compound of formulaX. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula X has the following formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1 and Z, L, R¹, R′″ are as defined above for a compound offormula X.

In some embodiments of a compound of formula X has the followingformulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are is H, C₁₋₆ alkyl, hal, —CF₃,—OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ are as defined above for acompound of formula X. In some embodiments, n is 0. In some embodiments,n is 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula X has the following formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ areas defined above for a compound of formula X. In some embodiments R^(a)and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments of a compound of formula X has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ areas defined above for a compound of formula X. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula X has the following formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R, R′″ areas defined above for a compound of formula X. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula X has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹, R′″ areas defined above for a compound of formula X. In some embodiments, n is0. In some embodiments, n is 1. In some embodiments R^(a) and R^(b) arehydrogen.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, or tetrahydrofuryl (e.g., C₁₋₄ alkyl).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl. In some embodiments, L is —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂— or —CH₂—C(CH₃)₂—.

In some embodiments of a compound of formula X, a 3 to 6-memberedheterocycloalkyl (in combination with —(NR⁴R⁵)) refers to a non-aromaticor partially aromatic ring system having 3, 4, 5, or 6 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula X, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g. 5ring atoms), selected from C, N, O, or S (e.g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like.

In some embodiments, examples of “heteroaryl” include pyrrolyl,imidazolyl.

In some embodiments of a compound of formula X, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.Examples of a 3 to 9-membered heterocycloalkyl (in combination with—(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl, thiaranyl,aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl) fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O; spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl).

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, examples of 3 to 9-membered heterocycloalkyl are

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), X is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁷ is —O—, —NH— or —N(CH₃)—,—SO₂ (e.g. 0).

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z isselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), and X⁷ is —O—,—NH— or —N(CH₃)—, —SO₂ (e.g. —O—).

In some embodiments, compound of formula X has the formula XI or XII

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;

R′″ is H or —CH₃;

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R^(a), R^(b) are independently of each other H, hal, or —CH₂O—CH₃ (e.g.H), and R_(e) is H or methyl.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, Li is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or XV is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring) orX³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl (e.g. C₁₋₄alkyl).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl. In some embodiments, L is —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂— or —CH₂—C(CH₃)₂—.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄˜ alkyl.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, or tetrahydrofuryl (e.g., methyl).

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂,

wherein R^(c) is H, C₁₋₄˜ alkyl, oxetane (e.g. H, —CH₃); X⁶ is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁷ is —O—, —NH— or —N(CH₃)—,—SO₂.

In some embodiments, —(CR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, 3 to 9-membered heterocycloalkyl are

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), X⁶ is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁷ is —O—, —NH— or —N(CH₃)—,—SO₂ (e.g. —O—).

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z areselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), and X⁷ is —O—,—NH— or —N(CH₃)—, —SO₂, (e.g. —O—).

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, -X¹-L¹- is —NH—. In some embodiments,-X¹-L¹- is —NH—CH₂—.

In some embodiments, the compound of formula XI or XII has the formulaXI-1, XII-1, or XI-2, XII-2

whereinX², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═, —CH═;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;

R′″ is H or —CH₃;

Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H); R_(e) is H or methyl and n is 0 or 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X³, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(3′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).In some embodiments, X²,X^(2′) are —CH═ (i.e. a phenyl ring). In some embodiments, X³, X^(3′),X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring) or X3 is —N═ and X^(3′),X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl (e.g. straight chain or branched C₁₋₄ alkyl).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal andR^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H.

In some embodiments, the compound of formula XI-1, XI-2 has one of thefollowing formulas

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R′″, R^(a), R^(b), R^(e)are as defined above for a compound of formula XI or XII (or XI-1,XII-1).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula XI-1, XII-1 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1, and Z, L, R′″,R^(a), R^(b), R^(e) are as defined above for a compound of formula XI orXII (or XI-1, XII-1).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(3′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, a compound of formula XI-2, XII-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R′″, R^(a), R^(b),R^(e) are as defined above for a compound of formula XI or XII (or XI-1,XII-1).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula XI-2, XII-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1; and Z, L, R′″,R^(a), R^(b), R^(e) are as defined above for a compound of formula XI orXII (or XI-1, XII-1).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, R² and R^(2′) are independently of each other (e.g.H, hal or C₁₋₆ alkyl and H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or—CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, a compound of formula XI-1, XII-1, or XI-2, XII-2has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R′″, R^(a), R^(b), R^(e) are as defined abovefor a compound of formula XI or XII (or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XI-1, XII-1 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R′″, R^(a), R^(b), R^(e) are as defined abovefor a compound of formula XI or XII (or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XI-2, XII-2 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′), are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R′″, R^(a), R^(b), R^(e) are as defined abovefor a compound of formula XI or XII (or XI-1, XII-1 or XI-2, XII-2) Insome embodiments, n is 0. In some embodiments, n is 1.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XI-1 has the formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1, or V-2, VI-2).

In some embodiments, R² is halogen, such as C1.

In some embodiments, R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XI-1, XII-1 has the formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R′″, R^(a),R^(b), R^(e) are as defined above for a compound of formula XI or XII(or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XI-2, XII-2 has the forms as

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R′″, R^(a),R^(b), R^(e) are as defined above for a compound of formula XI or XII(or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XI-2, XII-2 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R′″,R^(a), R^(b), R^(e) are as defined above for a compound of formula XI orXII (or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(h) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XI-2, XII-2 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R′″,R^(a), R^(b), R^(e) are as defined above for a compound of formula XI orXII (or XI-1, XII-1 or XI-2, XII-2).

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl (e.g. C₁₋₄ alkyl).

In some embodiments, L is a covalent bond, straight chain or branchedC₁₋₄ alkyl. In some embodiments, L is —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄— or —C(CH₃)₂—.

In some embodiments, group Z is defined as specified above. In someembodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of eachother H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —NR), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, the —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z areselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂, and

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z areselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃); X⁶ is H, —CH₃,—OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, Cl, and X⁷ is —O—, —NH— or —N(CH₃)—,—SO₂ (e.g. —O—).

In some embodiments, group Z is selected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane (e.g. H, —CH₃), and X⁷ is —O—,—NH— or —N(CH₃)—, —SO₂ (e.g. —O—).

In some embodiments, the present disclosure is directed towards acompound or pharmaceutically acceptable salts or stereoisomers thereofof formula I above wherein Y² is —C≡C— having the following formula XIII

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N—, —CH—;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R¹ is —CH═CH₂, —C≡CH or —C≡C—CH₃;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, or —(NR⁶R⁷)— or —(CHR⁶R⁷)—, wherein R⁶ and R⁷ form together withthe atom to which they are attached to 3 to 6-membered heteroaryl, or 3to 9-membered heterocycloalkyl, wherein the 3 to 9-memberedheterocycloalkyl is a monocycle or a fused, bridged or spirobicycle or acombination thereof, which is unsubstituted or substituted with C₁₋₄alkyl, hal, —OR′, —NR′R″, wherein R′, R″ are independently of each otherH or —C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(V) is —N═ and X³, X⁵, X^(5′), X⁶ are is —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, for the compounds of formula XIII, groups X²,X^(2′) are —CH═ (i.e. a phenyl ring). In some embodiments, X³, X^(3′),X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring). In some embodiments, X³ is—N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ or X³ is —N═ and X³, X⁵, X^(5′),X⁶ are —CH═(i.e. a pyridine ring).

In some embodiments, for the compounds of formula XIII, group L is acovalent bond or straight chain or branched C₁₋₄ alkyl.

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl).

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, for the compounds of formula XIII, groups R² andR^(2′) are H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H,hal; or R² and R^(2′) are hal and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃and R^(3′) is H, hal; or R² is hal or C₁₋₆ alkyl and R^(2′) is H and R³is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H; or R² is hal or C₁₋₆alkyl and R^(2′) is H and R^(3′) is C₁₋₆ alkyl, hal and R³ is H.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)- and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, compound XIII has the following formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X^(6′) is —N═and X³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal, (e.g. H, —CH₃, F, Cl). In some embodiments, R³ andR^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R′″ is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal or C₁₋₆alkyl and R^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ andR^(3′) is H; or R² is hal or C₁₋₆ alkyl and R² is H and R^(3′) is C₁₋₆alkyl, hal and R³ is H.

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl.

In some embodiments, a compound of formula XIII has one of the followingformulas

wherein W is

wherein X², X^(2′) and X³, X^(3′), X⁶ are independently of each other—N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; and Z, L, R¹are as defined above for a compound of formula XIII. In someembodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═(i.e a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, the compound of formula XIII has the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′), X⁵, X^(5′), X⁶ are —N═ and X⁵, X³,X⁶ are —CH═ or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e.a pyridazine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵,X⁶ are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e.a pyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X³ is—N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl.

In some embodiments, -X¹-L¹- is —NH—. In some embodiments, -X¹-L¹- is—NH—CH₂—. In some embodiments, a compound of formula XIII has thefollowing formula

wherein X², X^(2′) and X³, X^(3′), X⁵, X^(5′), X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′) and R³, R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, and n is 0, 1, 2, 3; andZ, L, R¹ are as defined above for a compound of formula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X^(6′) are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl.

R² and R^(2′) are independently of each other H, C₁₋₆ alkyl, hal, (e.g.H, —CH₃, F, Cl). In some embodiments, R³ and R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal or C₁₋₆alkyl and R^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ andR^(3′) is H; or R² is hal or C₁₋₆ alkyl and R^(2′) is H and R^(3′) isC₁₋₆ alkyl, hal and R³ is H.

In some embodiments, a compound of formula XIII has one of the followingformulas

wherein W is

X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and n is 0 or 1; and Z, L, R¹ are as definedabove for a compound of formula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula XIII has the followingformulas

wherein W is

wherein X², X^(2′), X³, X^(3′), X⁶ are independently of each other —N═or —CH═; and R², R^(2′), R³, R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X³, X^(3′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl.

In some embodiments, R² and R^(2′) are independently of each other H,hal or C₁₋₆ alkyl (e.g. H, hal or —CH₃).

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃.

In some embodiments, R³ is H, hal or C₁₋₆ alkyl, (e.g. H, hal or —CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ andR^(3′) are hal. In some embodiments, R³ is hal, —CF₃, or —OCF₃ andR^(3′) is H. In some embodiments, R³ is H and R^(3′) is hal, or C₁₋₆alkyl.

In some embodiments, R² and R^(2′) are H. In some embodiments, R² andR^(2′) are hal. In some embodiments, R² is hal or C₁₋₆ alkyl and R^(2′)is H. In some embodiments, R² is H and R^(2′) is hal.

In some embodiments, a compound of formula XIII has the followingformula

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula XIII. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XIII has the followingformulas

wherein R², R^(2′) are independently of each other H, C₁₋₆alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula XIII.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula XIII has the followingformulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R¹ are as defined above for a compound offormula VI. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XIII has the followingformula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula XIII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl), R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula XIII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl), R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula XIII has the followingformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R¹ are asdefined above for a compound of formula XIII. In some embodiments, n is0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl.

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —C(CH₃)₂— or—CH₂—C(CH₃)₂—).

In some embodiments of a compound of formula XIII, a 3 to 6-memberedheterocycloalkyl (in combination with —(NR⁴R⁵)) refers to a non-aromaticor partially aromatic ring system having 3, 4, 5, or 6 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 and the number of O and S atoms each being 0, 1, 2.Examples of 3 to 6-membered heterocycloalkyl groups include oxiranyl,thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl and the like. In someembodiments, 3 to 6-membered heterocycloalkyl include 5-memberedheterocycloalkyl having 1 or 2 O-atoms, such as oxiranyl, oxetanyl,tetrahydrofuranyl, dioxanyl.

In some embodiments of a compound of formula XIII, a 3 to 6-memberedheteroaryl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to a(fully) aromatic ring system having 3, 4, 5, or 6 ring atoms (e.g. 5ring atoms), selected from C, N, O, or S (e g. C, N, or O, and C or N,with the number of N atoms being 0, 1, 2 or 3 and the number of O and Satoms each being 0, 1 or 2). Examples of “heteroaryl” include furyl,imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl),pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, andthe like. In some embodiments, examples of “heteroaryl” includepyrrolyl, imidazolyl. Preferably, the aromatic ring system is a nitrogencontaining heteroaryl.

In some embodiments of a compound of formula XIII, a 3 to 9-memberedheterocycloalkyl (in combination with —(NR⁶R⁷) or —(CHR⁶R⁷)) refers to anon-aromatic or partially aromatic ring system having 3 to 9 ring atomsselected from C, N, O, or S (e.g. C, N, or O), the number of N atomsbeing 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2.Examples of a 3 to 9-membered heterocycloalkyl (in combination with—(NR⁶R⁷) or —(CHR⁶R⁷)) include monocycles such as oxiranyl, thiaranyl,aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl,dioxothiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl,azepanyl, diazepanyl, oxazepanyl (e.g. azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepanyl); fused ring systems,such as 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.3.0]octyl,3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl,2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl,2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl,4,9-diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl,3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl,3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl,3-thia-8-azabicyclo[4.3.0]nonyl, and the like; bridged ring systems suchas bicyclo[3.3.1]nonanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl (e.g.bicyclo[3.2.1]octanyl, bicyclo[2.2.1]heptanyl), having one or twoheteroatoms selected from N and O, spiro ring systems such asspiropentanyl, spiro[2.3]hexanyl spiro[3.3]heptanyl, spiro[3.4]octanyl,spiro[4.4]nonanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, (e.g.spiro[3.3]heptanyl, spiro[4.4]nonanyl), having one or two heteroatomsselected from N and O, (e.g. diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, diazaspiro[4.4]nonanyl,oxa-azaspiro[4.4]nonanyl). Preferably, the 3 to 9-memberedheterocycloalkyl contains at least one nitrogen atom. In someembodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of eachother H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CHR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, —(NHR⁶R⁷) and —(CHR⁶R⁷) include

wherein R^(c) is H, C₁₋₄ alkyl (e.g. H, —CH₃); X⁶ is H, C₁₋₄ alkyl (e.g.H, —CH₃); X⁷ is —O—, —NH— or —N(CH₃)—, (e.g. —N(CH₃)—).

In some embodiments, the compound of formula XIII has the formula XIV orXV

wherein X¹ is —O—, —CH₂—, —NH—, —S—; X², X^(2′), X³, X^(3′), X⁵, X^(5′),X⁶ are independently of each other —N═, —CH═;L¹ is a covalent bond or straight chain or branched C₁₋₃alkyl, which isunsubstituted or substituted with hal,R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃;L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4;Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl;R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H), and R_(e) is H or methyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, L¹ is straight chain or branched C₁₋₃alkyl, whichis unsubstituted or substituted with hal. In some embodiments, L¹ is nota covalent bond.

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X^(5′), X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridinering).

In some embodiments, R² and R^(2′) are independently of each other H,C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl). In some embodiments, R² andR^(2′) are H. In some embodiments, R² and R^(2′) are hal. In someembodiments, R² is hal and R^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal or C₁₋₆alkyl and R^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ andR^(3′) is H; or R² is hal or C₁₋₆ alkyl and R^(2′) is H and R^(3′) isC₁₋₆ alkyl, hal and R³ is H.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl (e.g. C₁₋₄alkyl).

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —C(CH₃)₂— or—CH₂—C(CH₃)₂—).

Group Z is as defined above. In some embodiments, Z is —(NR⁴R⁵), whereinR⁴ and R⁵ are independently of each other H, C₁₋₆ alkyl, cyclopropyl,cylobutyl, 3 to 6-membered heterocycloalkyl containing 0, 1, or 2N-atoms and 0, 1, or 2 O-atoms, or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ andR⁷ form together with the atom to which they are attached to 3 to6-membered heteroaryl containing 0, 1, 2 or 3 N-atoms and 0, 1, or 2O-atoms or 3 to 9-membered heterocycloalkyl containing 0, 1, 2 or 3N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to 9-memberedheterocycloalkyl is a monocycle or a fused, bridged or spirobicycle or acombination thereof, and is unsubstituted or substituted with C₁₋₄alkyl, hal, —OR′, —NR′R″, wherein R′, R″ are independently of each otherH or —C₁₋₄ alkyl.

In some embodiments, —(NR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂.

In some embodiments, —(CR⁶R⁷) ring systems include

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, —(NHR⁶R⁷) and —(CHR⁶R⁷) include

wherein R^(c) is H, C₁₋₄ alkyl (e.g. H, —CH₃); X⁶ is H, C₁₋₄ alkyl (e.g.H, —CH₃); X⁷ is —O—, —NH— or —N(CH₃)— (e.g. —N(CH₃)—).

In some embodiments, L is a covalent bond. In some embodiments, L isstraight chain or branched C₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —C(CH₃)₂— or —CH₂—C(CH₃)₂—). In some embodiments, L is

wherein m1, m2 are independently of each other 0, 1 or 2.

In some embodiments, X¹ is —O—. In some embodiments, X¹ is —CH₂—. Insome embodiments, X¹ is —NH—. In some embodiments, X¹ is —S—. In someembodiments, L¹ is a covalent bond. In some embodiments, L¹ is —CH₂— or—CH(CH₃)— or —CH(hal)-. In some embodiments, L¹ is —CH₂—CH₂— or—CH₂—CH(CH₃)— or —CH₂—CH(hal)-.

In some embodiments, linker combinations -X¹-L¹- include —O—, —CH₂—,—O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, —CH₂—CH(CH₃)—,—NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-, —CH₂—CH(hal)-, —NH—CH(hal)-,—S—CH(hal)- (e.g. —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—,—CH₂—CH(CH₃)—, —O—CH(hal)-, or —CH₂—CH(hal)-, and —O—, —CH₂—, —O—CH₂—,—NH—CH₂—, or —CH₂—CH₂—).

In some embodiments, -X¹-L¹- is —O—, In some embodiments, -X¹-L¹- is—O—CH₂—. In some embodiments, -X¹-L¹- is —NH—. In some embodiments,-X¹-L¹- is —NH—CH₂—.

In some embodiments, the compound of formula XIV and XV has the formulaXIV-1, XV-1 and XIV-2, XV-2

whereinX², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═, —CH═;R², R^(2′), R³, R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃; L is a covalent bond, straight chain or branched C₁₋₄alkyl or

wherein m1, m2 are independently of each other 0, 1, 2, 3, or 4 (e.g. acovalent bond, straight chain or branched C₁₋₄ alkyl);Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H, C₁₋₆alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl, or—(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl or 3 to 9-memberedheterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl is amonocycle or a fused, bridged or spirobicycle or a combination thereof,and is unsubstituted or substituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″,wherein R′, R″ are independently of each other H or —C₁₋₄ alkyl:R^(a), R^(b) are independently of each other H, hal, or —CH₂—O—CH₃ (e.g.H), and R_(e) is H or methyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or XV is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring).

R² and R^(2′) are independently of each other H, C₁₋₆ alkyl, hal (e.g.H, —CH₃, F, Cl). In some embodiments, R² and R^(2′) are H. In someembodiments, R² and R^(2′) are hal. In some embodiments, R² is hal andR^(2′) is H.

In some embodiments, R³ and R^(3′) are independently of each other H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃. In some embodiments, R³ is H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃ and R^(3′) is H, hal.

In some embodiments, R² and R^(2′) are H and R³ is H, C₁₋₆ alkyl, hal,—CF₃, —OCF₃ and R^(3′) is H, hal; or R² and R^(2′) are hal and R³ is H,C₁₋₆ alkyl, hal, —CF₃, —OCF₃ and R^(3′) is H, hal; or R² is hal or C₁₋₆alkyl and R^(2′) is H and R³ is H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃ andR^(3′) is H; or R² is hal or C₁₋₆ alkyl and R^(2′) is H and R^(3′) isC₁₋₆ alkyl, hal and R³ is H.

In some embodiments, the compound of XIV-1, XV-1 has one of thefollowing formulas

X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of each otherH, C₁₋₆alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(a), R^(b), R^(e) are asdefined above for a compound of formula XIV and XV (or XIV-1, XV-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X, are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula XIV-1, XV-1 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula XIV and XV(or XIV-1, XV-1).

In some embodiments substituent Z-L contains at least: one nitrogenatom. Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X³ is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ and X³,X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X^(6′) are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶are —CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring). Insome embodiments, a compound of formula XIV-2, XV-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and Z, L, R^(a), R^(b), R^(e)are as defined above for a compound of formula XIV and XV (or XIV-2,XV-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) are —CH═ (i.e. a phenyl ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, X² and X^(2′) are —N═ (i.e. a pyridine ring) andX³, X^(3′) and X⁶ are —CH═ (i.e. a phenyl ring).

In some embodiments, X² and X^(2′) a —N═ (i.e. a pyridine ring) and X³,X^(3′) and X⁶ are —N═ (i.e. a pyridine ring).

In some embodiments, a compound of formula XI-2, XV-2 has one of thefollowing formulas

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), X⁶ are independently of eachother —N═ or —CH═; and R², R^(2′), R³, R^(3′) are independently of eachother H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃, n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula XIV and XV(or XIV-1, XV-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, both X², X^(2′) are —CH═ (i.e. a phenyl ring). Insome embodiments, X² is —N═ and X^(2′) is —CH═ or X^(2′) is —N═ and X²is —CH═ (i.e. a pyridine ring). In some embodiments, both X², X^(2′) are—N═ (i.e. a pyridazine ring).

In some embodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenylring). In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are—CH═ or X^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ or X⁶ is —N═ andX³, X^(3′), X⁵, X^(5′) are —CH═ (i.e. a pyridine ring).

In some embodiments, both X³, X^(3′) are —N═ and X⁵, X^(5′), X⁶ are —CH═or both X^(3′), X⁶ are —N═ and X³, X⁵, X^(5′) are —CH═ (i.e. apyridazine ring). In some embodiments, both X³, X⁵ are —N═ and X^(3′),X^(5′), X⁶ are —CH═ or both X^(3′), X^(5′) are —N═ and X³, X⁵, X⁶ are—CH═ or both X³, X⁶ are —N═ and X^(3′), X⁵, X^(5′) are —CH═ (i.e. apyrimidine ring). In some embodiments, both X³, X^(5′) are —N═ andX^(3′), X⁵, X⁶ are —CH═ (i.e. a pyrazine ring).

In some embodiments, X², X^(2′) are —CH═ (i.e. a phenyl ring). In someembodiments, X³, X^(3′), X⁵, X^(5′), X⁶ are —CH═ (i.e. a phenyl ring).In some embodiments, X³ is —N═ and X^(3′), X⁵, X^(5′), X⁶ are —CH═ orX^(3′) is —N═ and X³, X⁵, X^(5′), X⁶ are —CH═ (i.e. a pyridine ring). R²and R^(2′) are independently of each other H, hal or C₁₋₄ alkyl (e.g. H,hal or —CH₃).

In some embodiments, R² and R^(2′) are H. In some embodiments, R² is halor C₁₋₆ alkyl and R² is H. In some embodiments, R² is H and R² is hal.In some embodiments, R² and R^(2′) are hal.

In some embodiments, R³ is H, hal, —CF₃, or —OCF₃. In some embodiments,R^(3′) is H, hal or C₁₋₆ alkyl (e.g. H, hal or —CH₃).

In some embodiments, R³ and R^(3′) are H. In some embodiments, R³ is Hand R^(3′) is hal, or C₁₋₆ alkyl (e.g. C₁₋₆ alkyl). In some embodiments,R³ is hal, —CF₃, or —OCF₃ and R^(3′) is H.

In some embodiments, a compound of formula XIV-1, XV-1, or XIV-2, XV-2has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula XIV and XV (or XIV-1, XV-1, or XIV-2, XV-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(E) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is I.

In some embodiments of a compound of formula XIV-1, XV-1 has theformulas

wherein R², R^(2′).are independently of each other H, C₁₋₆ alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃;and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as defined above fora compound of formula XIV and XV (or XIV-1, XV-1, or XIV-2, XV-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XIV-1 has the formula

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula V and VI (orV-1, VI-1, or V-2, VI-2).

In some embodiments, R² is halogen, such as C1.

In some embodiments, R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XIV-2, XV-2 has the formulas

wherein R², R^(2′) are independently of each other H, C₁₋₆alkyl, hal(e.g. H, —CH₃, F, Cl); R³, R^(3′) are is H, C₁₋₆ alkyl, hal, —CF₃,—OCF₃; and n is 0 or 1; and Z, L, R^(a), R^(b), R^(e) are as definedabove for a compound of formula XIV, XV (or XIV-2, XV-2). In someembodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments of a compound of formula XIV-1, XV-1 has theformulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areis H, C₁₋₆alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula XIV and XV(or XIV-1, XV-1).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CH—R₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XIV-2, XV-2 has the formulas

wherein R² is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) areH, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula XIV, XV (orXIV-2, XV-2). In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, a compound of formula XIV-1, XV-1 has the formulas

wherein R² is H, C₁₋₆alkyl, hal (e.g. H, —CH₃, F, Cl); R³, R^(3′) are isH, C₁₋₆alkyl, hal, —CF₃—OCF₃; and n is 0 or 1; and Z, L, R^(a), R^(b),R^(e) are as defined above for a compound of formula XIV, XV (or XIV-1,XV-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CH—R₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, a compound of formula XIV-2, XV-2 has the formulas

wherein R¹ is H, C₁₋₆ alkyl, hal (e.g. H, —CH₃, F, Cl), R³, R^(3′) areis H, C₁₋₆ alkyl, hal, —CF₃, —OCF₃; and n is 0 or 1; and Z, L, R^(a),R^(b), R^(e) are as defined above for a compound of formula XIV, XV (orXIV-2, XV-2).

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments R^(a) and R^(b) are hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, R⁴ and R⁵ are independently of each other H, C₁₋₄alkyl, cyclopropyl, tetrahydrofuryl (e.g. C₁₋₄ alkyl).

In some embodiments, L is a covalent bond or straight chain or branchedC₁₋₄ alkyl (e.g. —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —C(CH₃)₂— or—CH₂—C(CH₃)₂—).

In some embodiments, group Z is defined as specified above. In someembodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of eachother H, C₁₋₆ alkyl, cyclopropyl, cylobutyl, 3 to 6-memberedheterocycloalkyl containing 0, 1, or 2 N-atoms and 0, 1, or 2 O-atoms,or —(NR⁶R⁷), —(CHR⁶R⁷), wherein R⁶ and R⁷ form together with the atom towhich they are attached to 3 to 6-membered heteroaryl containing 0, 1, 2or 3 N-atoms and 0, 1, or 2 O-atoms or 3 to 9-membered heterocycloalkylcontaining 0, 1, 2 or 3 N-atoms and 0, 1, or 2 O-atoms, wherein the 3 to9-membered heterocycloalkyl is a monocycle or a fused, bridged orspirobicycle or a combination thereof, and is unsubstituted orsubstituted with C₁₋₄ alkyl, hal, —OR′, —NR′R″, wherein R′, R″ areindependently of each other H or —C₁₋₄ alkyl.

In some embodiments, —(CR⁶R⁷) and —(NR⁶R⁷) ring systems of Z areselected from

wherein R^(c) is H, C₁₋₄ alkyl, oxetane; X⁶ is H, —CH₃, —OH, —OCH₃,—OCF₃, —N(CH₃)₂, F, Cl; X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂, and

wherein R^(c) is H, C₁₋₄ alkyl, oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, —(CHR⁶R⁷)—, —(NR⁶R⁷) are selected from

wherein X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂; R^(c) is H, C₁₋₄ alkyl,oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments, compounds of XIII have formula XVI

wherein R¹ is —CH═CH₂, —C≡CH or —C≡C—CH₃; R² is H, C₁₋₄ alkyl (e.g.—CH₃, hal);L is a covalent bond or straight chain or branched C₁₋₄ alkyl (e.g.—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —C(CH₃)₂—);s Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independently of each other H,C₁₋₆ alkyl, or —(CHR⁶R⁷)—, —(NR⁶R⁷) wherein R⁶ and R⁷ form together withthe atom to which they are attached to 3 to 6-membered heteroaryl, or 3to 9-membered heterocycloalkyl, wherein the 3 to 9-memberedheterocycloalkyl is a monocycle or a fused bridged or spirobicycle or acombination thereof, which is unsubstituted or substituted with C₁₋₄alkyl.

In some embodiments, Z is —(NR⁴R⁵), wherein R⁴ and R⁵ are independentlyof each other H, C₁₋₆ alkyl, or —(CHR⁶R⁷)—, —(NR⁶R⁷) wherein R⁶ and R⁷form together with the atom to which they are attached to 3 to9-membered heterocycloalkyl, wherein the 3 to 6-memberedheterocycloalkyl is a monocycle, or fused fused bicycle, which isunsubstituted or substituted with C₁₋₄ alkyl.

In some embodiments, —(CHR⁶R⁷)—, —(NR⁶R⁷) are selected from

wherein X⁷ is —O—, —NH— or —N(CH₃)—, —SO₂; R^(c) is H, C₁₋₄ alkyl,oxetane, and R^(d) is H, C₁₋₄ alkyl.

In some embodiments substituent Z-L contains at least one nitrogen atom.Thus, the 3-6-membered heteroaryl or 3-9-membered heterocycloalkylformed by R₆ and R₇ of (CHR₆R₇) includes a nitrogen atom if L does notcontain a nitrogen atom.

In some embodiments, the compound is selected from the compoundsdescribed in Table I, pharmaceutically acceptable salts thereof, andstereoisomers thereof.

In some embodiments, the compound is selected from the compoundsdescribed in Table I and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from the compoundsdescribed in Table 1.

TABLE 1 Compound No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

The/compounds of the present disclosure can contain one or moreasymmetric centers in the molecule. A compound without designation ofthe stereochemistry is to be understood to include all the opticalisomers (e.g., diastereomers, enantiomers, etc) in pure or substantiallypure form, as well as mixtures thereof (e.g. a racemic mixture, or anenantiomerically enriched mixture). It is well known in the art how toprepare such optically active forms (e.g. by resolution of the racemicform by recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, by chromatographic separationusing a chiral stationary phase, and other methods).

The compounds can be isotopically-labeled compounds, for example,compounds including various isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, iodine, or chlorine. The disclosedcompounds may exist in tautomeric forms and mixtures and separateindividual tautomers are contemplated. In addition, some compounds mayexhibit polymorphism.

The compounds of the present disclosure include the free form as well asthe pharmaceutically acceptable salts and stereoisomers thereof. Thepharmaceutically acceptable salts include all the typicalpharmaceutically acceptable salts. The pharmaceutically acceptable saltsof the present compounds can be synthesized from the compounds of thepresent disclosure which contain a basic or acidic moiety byconventional chemical methods, see e.g. Berge et al, “PharmaceuticalSalts,” J. Pharm. ScL, 1977:66:1-19.

For example, conventional pharmaceutically acceptable salts for a basiccompound include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like, as well as salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like. Conventional pharmaceutically acceptablesalts for an acidic compound include those derived from inorganic basesinclude aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic salts, manganous, potassium, sodium, zinc and thelike. Salts derived from pharmaceutically acceptable organic basesinclude salts of primary, secondary and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic aminesand basic ion exchange resins, such as arginine, betaine caffeine,choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The compounds of the present disclosure may exist in solid, i.e.crystalline or noncrystalline form (optionally as solvates) or liquidform. In the solid state, it may exist in, or as a mixture thereof. Incrystalline solvates, solvent molecules are incorporated into thecrystalline lattice during crystallization. The formation of solvatesmay include non-aqueous solvents such as, but not limited to, ethanol,isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, oraqueous solvents such as water (also called “hydrates”). It is commonknowledge that crystalline forms (and solvates thereof) may exhibitpolymorphism, i.e. exist in different crystalline structures known as“polymorphs”, that have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties, and may display different meltingpoints, IR spectra, and X-ray powder diffraction patterns, which may beused for identification. Such different polymorphs may be produced, forexample, by changing or adjusting the reaction conditions or reagents,during preparation of the compound of the present disclosure.

Syntheses of Compounds

In some embodiments, the present disclosure provides methods ofpreparation of the compounds of the present disclosure. In someembodiments, the compounds are prepared according to the syntheses shownin schemes A to D in the experimental section.

In some embodiments, the present disclosure provides a method ofpreparing a compound of the present disclosure.

In some embodiments, the present disclosure provides a method of acompound, comprising one or more steps as described herein.

In some embodiments, the present disclosure provides a compoundobtainable by, or obtained by, or directly obtained by a method forpreparing a compound as described herein.

In some embodiments, the present disclosure provides an intermediate asdescribed herein, being suitable for use in a method for preparing acompound as described herein.

The compounds of the present disclosure can be prepared by any suitabletechnique known in the art. Processes for the preparation of thesecompounds are described in the accompanying examples.

In the description of the synthetic methods described herein and in anyreferenced synthetic methods that are used to prepare the startingmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilized.

It will be appreciated that during the synthesis of the compounds of thedisclosure in the processes defined herein, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed. For examplesof protecting groups see one of the many general texts on the subject,for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green(publisher: John Wiley & Sons). Protecting groups may be removed by anyconvenient method described in the literature or known to the skilledchemist as appropriate for the removal of the protecting group inquestion, such methods being chosen so as to effect removal of theprotecting group with the minimum disturbance of groups elsewhere in themolecule. Thus, if reactants include, for example, groups such as amino,carboxy or hydroxy it may be desirable to protect the group in some ofthe reactions mentioned herein.

As will be understood by the person skilled in the art of organicsynthesis, compounds of the present disclosure are readily accessible byvarious synthetic routes, some of which are exemplified in theaccompanying examples. The skilled person will easily recognize whichkind of reagents and reactions conditions are to be used and how theyare to be applied and adapted in any particular instance—wherevernecessary or useful—in order to obtain the compounds of the presentdisclosure. In some embodiments, some of the compounds of the presentdisclosure can readily be synthesised by reacting other compounds of thepresent disclosure under suitable conditions, for instance, byconverting one particular functional group being present in a compoundof the present disclosure, or a suitable precursor molecule thereof,into another one by applying standard synthetic methods, like reduction,oxidation, addition or substitution reactions; those methods are wellknown to the skilled person. Likewise, the skilled person willapply—whenever necessary or useful—synthetic protecting (or protective)groups; suitable protecting groups as well as methods for introducingand removing them are well-known to the person skilled in the art ofchemical synthesis and are described, in more detail, in, e.g., P.G.M.Wuts, T.W. Greene, “Greene's Protective Groups in Organic Synthesis”,4th edition (2006) (John Wiley & Sons).

General routes for the preparation of a compound of the application aredescribed in the general procedures A-D:

Step A.1:

A solution of 7-fluoro-6-nitro-quinazolin-4-ol (5.00 g, 23.9 mmol, 1.00eq) in thionyl chloride (20.0 mL) was added dimethyl formamide (174 mg,2.39 mmol, 183 uL, 0.10 eq). The reaction was stirred at 80° C. for 10h. The reaction mixture was concentrated under reduced pressure to give4-chloro-7-fluoro-6-nitroquinazoline (6.00 g, crude) as an off-whitesolid. The product was taken to next step without purification.

Step A.2:

A mixture of 4-chloro-7-fluoro-6-nitroquinazoline (2.4 g, 10.55 mmol, 1eq) and the free amine H₂N—X (1 eq) in isopropyl alcohol was heated at80° C. for 1 h. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was triturated with ethylacetate to give amine III.

Step A.3:

To a solution of amine III (1 eq) and the NH or OH nucleophile Z-L-Y²—H(1.1 eq) in acetonitrile was added cesium carbonate (2eq) or DBU (2eq)and optionally potassium iodide (1 eq). Then the mixture was stirred at80-110° C. for 12 h. The reaction mixture was quenched by addition ofwater and then extracted with ethyl acetate. The combined organic layerswere washed with brine dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography to give IV.

Step A.4:

Variant i): A mixture of IV (1 eq) and nickel(ii) chloride hexahydrate(2 eq) in dichloromethane and methanol (1:1) was added sodiumborohydride (4 eq) at 0° C. and then the mixture was stirred at 0° C.for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine V.

Variant ii): A mixture of IV (1 eq), iron (3 eq) and ammonium chloride(5 eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine V.

Step A.5:

Variant i): To a solution of V (1 eq), 4-dimethylaminopyridine (1.5 eq)and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide VI.

Variant ii): To a solution of V (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide VI.

Variant iii): To a solution of V (1.0 eq) in dimethylformamide was addedtriethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h and subsequently filtered.The filtrate was purified by prep-HPLC to give acrylamide VI.

Step A.6:

To a solution of V (1.0 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 eq)and pyridine (5.00 eq) in N,N-dimethylformamide was added but-2-ynoicacid (10.0 eq). The mixture was stirred at 50° C. for 2 h andsubsequently concentrated in vacuum. The mixture was purified byprep-HPLC to give ynamide VII.

To a solution of III, obtained in step A.2 (1.00 eq) and potassiumtert-butoxide (4.00 eq) in dimethylsulfoxide (10.0 mL) was added thecorresponding diol of aminoalcohol (6.00 eq) dropwise at 20° C. Themixture was stirred at 20° C. for 12 h. The mixture was diluted withwater and extracted with ethyl acetate. The combined organic layer waswashed with brine and dried over sodium sulfate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel chromatography to give alcohol VIII.

Step B.2:

Variant i): To a solution of VIII (1 eq) and triethylamine (4.00 eq) indichloromethane and dimethylsulfoxide (6:1) was added MsCl (4.00 eq)dropwise at 0° C. The mixture was stirred at 20° C. for 2 h. The mixturewas diluted with water and extracted with dichloromethane. The combinedorganic layer was washed with brine and dried over sodium sulfate,filtered and concentrated to give Mesylate IX.

Variant ii): To a solution of VIII (1.0 eq) in thionyl chloride wasadded N,N-dimethylformamide (0.1 eq). The mixture was stirred at 90° C.for 3 h. The mixture was cooled to 25° C. and then concentrated invacuum. The mixture was partitioned between and ethyl acetate. Theorganic phase was washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to afford chloride IX.

Step B.3:

To a solution of IX (1.0 eq) and potassium carbonate (4.00 eq) indimethylsulfoxide was the corresponding N—H nucleophile (2.0 eq) in oneportion at 20° C. The mixture was stirred at 50° C. for 12 h. Themixture was diluted with water and extracted with ethyl acetate. Thecombined organic layer was washed with brine and dried over sodiumsulfate, filtered and concentrated to give crude product. The crudeproduct was purified by prep-HPLC to give X.

Step B.4:

Variant i): A mixture of X (1 eq) and nickel(ii) chloride hexahydrate (2eq) in dichloromethane and methanol (1:1) was added sodium borohydride(4 eq) at 0° C. and then the mixture was stirred at 0° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated to givea residue. The residue was purified by reversed phase columnchromatography to give amine XI.

Variant ii): A mixture of X (1 eq), iron (3 eq) and ammonium chloride (5eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XI.

Step B.5:

Variant i): To a solution of XI (1 eq), 4-dimethylaminopyridine (1.5 eq)and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25′° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Variant ii): To a solution of XI (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25′C for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Variant iii): To a solution of XI (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Step C.1:

Sodium (3.0 eq) was added to the corresponding diol (18.7 eq) at 25′C.The suspension was stirred at 25° C. for 0.5 h. Alcohol 1 (1.0 eq) wasadded to the above suspension. The mixture was heated to 70° C. andstirred at 70° C. for 1.5 h. The mixture was cooled to 25° C. and thenadjusted to pH=7 with hydrochloric acid (3 M). After filtration, thefilter cake was dried under reduced pressure to afford diol XIII.

Step C.2:

To a solution of diol XIII (1.00 eq) in thionyl chloride (10.0 mL) wasadded N,N-dimethylformamide (0.1 eq). The mixture was stirred at 90° C.for 3 h. The mixture was cooled to 25° C. and then concentrated invacuum. The mixture was partitioned between water and ethyl acetate. Theorganic phase was washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to afford dichloride XIV.

Step C.3:

A solution of dichloride XIV (1.0 eq) and H₂N—X (1.50 eq) in propan-2-olwas stirred at 90° C. for 12 h. The mixture was cooled to 25° C. andthen concentrated in vacuum. The residue was triturated with methanol,then filtered and dried under reduced pressure to afford XV.

Step C.4:

To a solution of XV (1.0 eq), potassium iodide (0.1 eq) andtetrabutylammonium iodide (0.1 eq) in toluene was added HNR′R″ (3.00eq). The mixture was stirred at 110° C. for 12 h. The mixture was cooledto 25° C. and then concentrated in vacuum. The residue was trituratedwith water and filtered, the filter cake was dried in vacuum to affordXVI.

Step C.5:

Variant i): A mixture of XVI (1 eq) and nickel(ii) chloride hexahydrate(2 eq) in dichloromethane and methanol (1:1) was added sodiumborohydride (4 eq) at 0° C. and then the mixture was stirred at 0° C.for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine XVII.

Variant ii): A mixture of XVI (1 eq), iron (3 eq) and ammonium chloride(5 eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XVII.

Step C₁₋₆:

Variant i): To a solution of XVII (1 eq), 4-dimethylaminopyridine (1.5eq) and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Variant ii): To a solution of XVII (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Variant iii): To a solution of XVII (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Steps C.7.

To a solution of XVII (1.0 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 eq)and pyridine (5.00 eq) in N,N-dimethylformamide was added but-2-ynoicacid (10.0 eq). The mixture was stirred at 50° C. for 2 h andsubsequently concentrated in vacuum. The mixture was purified byprep-HPLC to give ynamide XIX.

Step D.1:

To a solution of bromide or triflate XX (1.00 eq) in dimethylsulfoxidewas added the corresponding alkyne (1.50 eq), triethylamine (3.00 eq),copper (I) iodide (0.5 eq), tetrakis(triphenylphosphine)palladium (0.05eq) at 20° C. The mixture was degassed with nitrogen and stirred at 20°C. for 12 h under nitrogen. The mixture was added methanol and filtered,the filter cake was concentrated to give alkyne XXI.

Step D.2:

To a suspension of alkyne XXI (1.00 eq) in thionyl chloride was addedN,N-dimethylformamide (2.0 eq) at 20° C. The mixture was stirred at 90°C. for 0.5 h until the suspension turned to homogenous solution. Thesolution was concentrated to give chloride XXII.

Step D.3:

A suspension of chloride XXII (1.0 eq) and H₂N—X in propan-2-ol wasstirred at 80° C. for 12 h. The mixture was concentrated to give aresidue. And the residue was purified by reverse phase chromatography togive XXIII.

Step D.4:

Variant i): A mixture of XXII (1 eq) and nickel(ii) chloride hexahydrate(2 eq) in dichloromethane and methanol (1:1) was added sodiumborohydride (4 eq) at 0° C. and then the mixture was stirred at 0° C.for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine XXIV.

Variant ii): A mixture of XXIII (1 eq), iron (3 eq) and ammoniumchloride (5 eq) in methanol and water (4:1) was stirred at 70° C. for 12h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XXIV.

Step D.5:

Variant i): To a solution of XXIV (1 eq), 4-dimethylaminopyridine (1.5eq) and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Variant ii): To a solution of XXIV (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Variant iii): To a solution of XXIV (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Pharmaceutical Compositions

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically-effective amount of one or moreof the compounds of the present disclosure or pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers and/or excipients (also referred to as diluents). Theexcipients are acceptable in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof (i.e., the patient). The term“therapeutically-effective amount” as used herein refers to the amountof a compound (as such or in form of a pharmaceutical composition) ofthe present disclosure which is effective for producing some desiredtherapeutic effect.

Pharmaceutical compositions may be in unit dose form containing apredetermined amount of a compound of the present disclosure per unitdose. Such a unit may contain a therapeutically effective dose of acompound of the present disclosure or salt thereof or a fraction of atherapeutically effective dose such that multiple unit dosage formsmight be administered at a given time to achieve the desiredtherapeutically effective dose. In some embodiments, unit dosageformulations are those containing a daily dose or sub-dose, or anappropriate fraction thereof, of a compound of the present disclosure orsalt thereof.

The compounds of the present disclosure may be administered by anyacceptable means in solid or liquid form, including (1) oraladministration, for example, drenches (i.e. aqueous or non-aqueoussolutions or suspensions), tablets, e.g., those targeted for buccal,sublingual, and systemic absorption, boluses, powders, granules, pastesfor application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8)nasally; (9) pulmonary; or (10) intrathecally.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical compositions.

Such compositions may contain components conventional in pharmaceuticalpreparations, e.g. wetting agents, emulsifiers and lubricants, such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, release agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants, pH modifiers, bulkingagents, and additional active agents. Examples ofpharmaceutically-acceptable antioxidants include: (1) water solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Such compositions may be prepared by any method known in the art, forexample, by bringing into association the active ingredient with one ormore carriers and/or excipients. Different compositions and examples ofcarriers and/or excipients are well known to the skilled person and aredescribed in detail in, e.g., Remington: The Science and Practice ofPharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn. Handbook ofPharmaceutical Excipients. Pharmaceutical Press, 2009. Excipients thatmay be used in the preparation of the pharmaceutical compositions mayinclude one or more of buffers, stabilizing agents, surfactants, wettingagents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide a composition suitable for anadministration of choice.

As indicated above, the compounds of the present disclosure may be insolid or liquid form and administered by various routes in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc.

In solid dosage forms of the present disclosure for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), a compound is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds andsurfactants, such as poloxamer and sodium lauryl sulfate; (7) wettingagents, such as, for example, cetyl alcohol, glycerol monostearate, andnon-ionic surfactants; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, zincstearate, sodium stearate, stearic acid, and mixtures thereof; (10)coloring agents; and (11) controlled release agents such as crospovidoneor ethyl cellulose. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-shelled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like. A tablet may be made by compression or molding, optionallywith one or more accessory ingredients. Compressed tablets may beprepared using binder (for example, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (forexample, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface-active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets, and other soliddosage forms of the pharmaceutical compositions of the presentdisclosure, such as dragees, capsules, pills and granules, mayoptionally be scored or prepared with coatings and shells, such asenteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeingredient can also be in micro-encapsulated form, if appropriate, withone or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of thepresent disclosure include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. An oral composition canalso include adjuvants such as wetting agents, emulsifying andsuspending agents, sweetening, flavoring, coloring, perfuming andpreservative agents.

In form of suspensions, a compound may contain suspending agents as, forexample, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar and tragacanth, and mixtures thereof.

Dosage forms for rectal or vaginal administration of a compound of thepresent disclosure include a suppository, which may be prepared bymixing one or more compounds of the present disclosure with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound. Other suitable forms include pessaries, tampons,creams, gels, pastes, foams or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof the present disclosure include powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. The activecompound may be mixed under sterile conditions with apharmaceutically-acceptable carrier, and with any preservatives,buffers, or propellants which may be required. Such ointments, pastes,creams and gels may contain, in addition to a compound of the presentdisclosure, excipients, such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Dosage forms such as powders and sprays for administration of a compoundof the present disclosure, may contain excipients such as lactose, talc,silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. Sprays can additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

Dosage forms such as transdermal patches for administration of acompound of the present disclosure may include absorption enhancers orretarders to increase or decrease the flux of the compound across theskin. The rate of such flux can be controlled by either providing a ratecontrolling membrane or dispersing the compound in a polymer matrix orgel. Other dosage forms contemplated include ophthalmic formulations,eye ointments, powders, solutions and the like. It is understood thatall contemplated compositions must be stable under the conditions ofmanufacture and storage, and preserved against the contaminating actionof microorganisms, such as bacteria and fungi.

The dosage levels of a compound of the present disclosure in thepharmaceutical compositions of the present disclosure may be adjusted inorder to obtain an amount of a compound of the present disclosure whichis effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing deleterious to the patient. The dosage of choice will depend upona variety of factors including the nature of the particular compound ofthe present disclosure used, the route of administration, the time ofadministration, the rate of excretion or metabolism of the particularcompound used, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts. A medical practitioner havingordinary skill in the art can readily determine and prescribe theeffective amount of the pharmaceutical composition required.

In some embodiments, a suitable daily dose of a compound of the presentdisclosure will be that amount of the compound which is the lowest doseeffective to produce a therapeutic effect. Such an effective dose willgenerally depend upon the factors described above. In some embodiments,oral, intravenous, intracerebroventricular and subcutaneous doses of thecompounds of the present disclosure for a patient, when used for theindicated analgesic effects, will range from about 0.0001 to about 100mg, more usual 0.1 to 100 mg/kg per kilogram of body weight of recipient(patient, mammal) per day. In some embodiments, daily dosages may befrom about 1 to about 1000 mg/day, and for example, from about 1 toabout 100 mg/day.

The effective dose of a compound of the present disclosure may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout a specifiedperiod (per day or per week or per month), optionally, in unit dosageforms. In some embodiments, dosing also depends on factors as indicatedabove, e.g. on the administration, and can be readily arrived at by oneskilled in medicine or the pharmacy art.

The compounds of the present disclosure inhibit or modulate the activityof a receptor tyrosine kinase, in particular extracellular mutants ofErbB-receptors, such as, but not limited to, EGFR-Viii (also EGFR-V3)and HER2-S310F. Thus, the compounds and compositions of the presentdisclosure can be useful as a medicament, i.e. as a medicament intherapy, for the treatment of cancer, as detailed below. In someembodiments, the present disclosure provides a method of treatment of amammal, for example, a human, suffering from cancer, as detailed below.The term “treatment” is intended to encompass prophylaxis, therapy andcure. Such treatment comprises the step of administering atherapeutically effective amount of a compound of Formula I or saltthereof (or of a pharmaceutical composition containing a compound ofFormula I or salt thereof) to said mammal, for example, a human.

Thus, the present disclosure is directed towards the use of thecompounds of the present disclosure or pharmaceutically acceptable saltsor stereoisomers thereof or a pharmaceutical composition thereof for thetreatment of cancer, as detailed below, in a mammal, for example ahuman.

In some embodiments, a use (or method of treatment) of a subjectcomprises administering to a subject in need of such treatment atherapeutically effective amount of a compound of the present disclosureor pharmaceutically acceptable salts thereof or a pharmaceuticalcomposition thereof by targeting allosteric and/or oncogenic variants ofEGFR and HER-2 receptor.

The present disclosure contemplates administration of a compound of thepresent disclosure alone or in combination with one or more additionaltherapeutic agents, such as other Tyrosine kinase inhibitors: Erlotinibhydrochloride (e.g. Tarceva® by Genentech/Roche), Linifanib (or ABT 869,by Genentech), sunitinib malate (e.g. Sutent® by Pfizer), bosutinib (orSKI-606, described in U.S. Pat. No. 6,780,996), dasatinib (e.g. Sprycel®by Bristol-Myers Squibb), armala (e.g. pazopanib, e.g. Votrient® byGlaxoSmithKline), imatinib and imatinib mesylate (e.g. Gilvec® andGleevec® by Novartis); Vascular Endothelial Growth Factor (VEG) receptorinhibitors (Bevacizumab, or Avastin® by Genentech/Roche), axitinib, (orAG013736, described in WO 01/002369), Brivanib Alaninate (orBMS-582664), motesanib (or AMG-706, described in PCT WO 02/066470),pasireotide (e.g. SOM230, described in WO 02/010192), sorafenib (e.g.Nexavar®); HER2 receptor inhibitors: Trastuzumab (e.g. Herceptin® byGenentech/Roche), neratinib (or HKI-272, described WO 05/028443),lapatinib or lapatinib ditosylate (e.g. Tykerb® by GlaxoSmithKline);CD20 antibodies: Rituximab (e.g. Riuxan® and MabThera® byGenentech/Roche), tositumomab (e.g. Bexxar® by GlaxoSmithKline), ofatumumab (e.g. Arzerra® by GlaxoSmithKline); Bcr/Abl kinase inhibitors:nilotinib hydrochloride (e.g. Tasigna® by Novartis); DNA Synthesisinhibitors: Capecitabine (e.g. Xeloda® by Roche), gemcitabinehydrochloride (e.g. Gemzar® by Eli Lilly and Company), nelarabine (orArranon® and Atriance® by GlaxoSmithKline); Antineoplastic agents:oxaliplatin (e.g. Eloxatin® by Sanofi-Aventis described in U.S. Pat. No.4,169,846); Epidermal growth factor receptor (EGFR) inhibitors:Gefitinib (or Iressa®), Afatinib (or Tovok® by Boehringer Ingelheim),cetuximab (e.g. Erbitux® by Bristol-Myers Squibb), panitumumab (e.g.Vectibix® by Amgen); HER dimerization inhibitors: Pertuzumab (e.g.Omnitarg®, by Genentech); Human Granulocyte colony-stimulatingfactor(G-CSF) modulators: Filgrastim (e.g. Neupogen® by Amgen);Immunomodulators: Afutuzumab (by Roche®), pegfilgrastim (e.g. Neulasta®by Amgen), lenalidomide (e.g. CC-5013, e.g. Revlimid®), thalidomide(e.g. Thalomid®); (m) CD40 inhibitors: Dacetuzumab (e.g. SGN-40 orhuS2C6, by Seattle Genetics, Inc); Pro-apoptotic receptor agonists(PARAs): Dulanermin (e.g. AMG-951, by Amgen/Genentech); Hedgehogantagonists: Vismodegib (or GDC-0449, described in WO 06/028958); PI3Kinhibitors: Pictilisib (or GDC-0941 described in WO 09/036082 and WO09/055730), Dactolisib (or BEZ 235 or NVP-BEZ 235, described in WO06/122806); Phospholipase A2 inhibitors: Anagrelide (e.g. Agrylin®);BCL-2 inhibitors: Navitoclax (or ABT-263, described in WO 09/155386);Mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (CasNo. 1029872-29-4, by ACC Corp.); Aromatase inhibitors: Exemestane (e.g.Aromasin® by Pfizer), letrozole (e.g. Femara® by Novartis), anastrozole(e.g. Arimidex®); Topoisomerase I inhibitors: Irinotecan (e.g.Camptosar® by Pfizer), topotecan hydrochloride (e.g. Hycamtin® byGlaxoSmithKline); Topoisomerase II inhibitors: etoposide (e.g. VP-16 andEtoposide phosphate, e.g. Toposar®, VePesid® and Etopophos®), teniposide(e.g. VM-26, e.g. Vumon®); mTOR inhibitors: Temsirolimus (e.g. Torisel®by Pfizer), ridaforolimus (formally known as deferolimus, (or AP23573and MK8669, described in WO 03/064383), everolimus (e.g. Afinitor® byNovartis); Osteoclastic bone resorption inhibitors: zoledronic acid (orZometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumabozogamicin (e.g. Mylotarg® by Pfizer/Wyeth); CD22 Antibody DrugConjugates: Inotuzumab ozogamicin (also referred to as CMC-544 andWAY-207294, by Hangzhou Sage Chemical Co., Ltd.); CD20 Antibody DrugConjugates: Ibritumomab tiuxetan (e.g. Zevalin®); Somatostain analogs:octreotide (e.g. octreotide acetate, e.g. Sandostatin® and SandostatinLAR®); Synthetic Interleukin-11 (IL-11): oprelvekin (e.g. Neumega® byPfizer/Wyeth); Synthetic erythropoietin: Darbepoetin alfa (e.g. Aranesp®by Amgen); Receptor Activator for Nuclear Factor kappa B (RANK)inhibitors: Denosumab (e.g. Prolia® by Amgen); Thrombopoietin mimeticpeptibodies: Romiplostim (e.g. Nplate® by Amgen; Cell growthstimulators: Palifermin (e.g. Kepivance® by Amgen); Anti-Insulin-likeGrowth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (e.g.CP-751,871, by ACC Corp), robatumumab (CAS No. 934235-44-6); Anti-CS1antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3); CD52 antibodies:Alemtuzumab (e.g. Campath®); CTLA-4 inhibitors: Tremelimumab (IgG2monoclonal antibody by Pfizer, formerly known as ticilimumab,CP-675,206), ipilimumab (CTLA-4 antibody, e.g. MDX-010, CAS No.477202-00-9); Histone deacetylase inhibitors (HDI): Voninostat (e.g.Zolinza® by Merck); Alkylating agents: Temozolomide (e.g. Temodar® andTemodal® by Schering-Plough/Merck), dactinomycin (e.g. actinomycin-D ande.g. Cosmegen®), melphalan (e.g. L-PAM, L-sarcolysin, and phenylalaninemustard, e.g. Alkeran®), altretamine (e.g. hexamethylmelamine (HMM),e.g. Hexalen®), carmustine (e.g. BiCNU®), bendamustine (e.g. Treanda®),busulfan (e.g. Busulfex® and Myleran®), carboplatin (e.g. Paraplatin®),lomustine (e.g. CCNU, e.g. CeeNU®), cisplatin (e.g. CDDP, e.g. Platinol®and Platinol®-AQ), chlorambucil (e.g. Leukeran®), cyclophosphamide (e.g.Cytoxan® and Neosar®), dacarbazine (e.g. DTIC, DIC and imidazolecarboxamide, e.g. DTIC-Dome®), altretamine (e.g. hexamethylmelamine(HMM) e.g. Hexalen®), ifosfamide (e.g. Ifex®), procarbazine (e.g.Matulane®), mechlorethamine (e.g. nitrogen mustard, mustine andmechloroethamine hydrochloride, e.g. Mustargen®), streptozocin (e.g.Zanosar®), thiotepa (e.g. thiophosphoamide, TESPA and TSPA, e.g.Thioplex®; Biologic response modifiers; bacillus calmette-guerin (e.g.theraCys® and TICE® BCG), denileukin diftitox (e.g. Ontak®); Anti-tumorantibiotics: doxorubicin (e.g. Adriamycin® and Rubex®), bleomycin (e.g.Lenoxane®), daunorubicin (e.g. dauorubicin hydrochloride, daunomycin,and rubidomycin hydrochloride, e.g. Cerubidine®), daunorubicin liposomal(daunorubicin citrate liposome, e.g. DaunoXome®), mitoxantrone (e.g.DHAD, e.g. Novantrone®), epirubicin (e.g. Ellence™), idarubicin (e.g.Idamycin®, Idamycin PFS®), mitomycin C (e.g. Mutamycin®);Anti-microtubule agents: Estramustine (e.g. Emcyl®); Cathepsin Kinhibitors: Odanacatib (or MK-0822, by Lanzhou Chon Chemicals, ACCCorp., and ChemieTek, described in WO 03/075836); Epothilone B analogs:Ixabepilone (e.g. Lxempra® by Bristol-Myers Squibb); Heat Shock Protein(HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin,e.g. KOS-953 and 17-AAG, by SIGMA, described in U.S. Pat. No.4,261,989); TpoR agonists: Eltrombopag (e.g. Promacta® and Revolade® byGlaxoSmithKline); Anti-mitotic agents: Docetaxel (e.g. Taxotere® bySanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (e.g.Cytadren®); Anti-androgens: Nilutamide (e.g. Nilandron® and Anandron®),bicalutamide (sold under tradename Casodex®), flutamide (e.g. Fulexin™);Androgens: Fluoxymesterone (e.g. Halotestin®); Proteasome inhibitors:Bortezomib (e.g. Velcade®); CDK1 inhibitors: Alvocidib (e.g. flovopirdolor HMR-1275, described in U.S. Pat. No. 5,621,002);Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide orleuprolide acetate (e.g. Viadure® by Bayer AG, Eligard® bySanofi-Aventis and Lupron® by Abbott Lab); Taxane anti-neoplasticagents: Cabazitaxel, larotaxel; 5HT1a receptor agonists: Xaliproden (orSR57746, described in U.S. Pat. No. 5,266,573); HPC vaccines: Cervarix®sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents:Deferasinox (e.g. Exjade® by Novartis); Anti-metabolites: Claribine(2-chlorodeoxyadenosine, e.g. Leustatin®), 5-fluorouracil (e.g.Adrucil®), 6-thioguanine (e.g. Purinethol®), pemetrexed (e.g. Alimta®),cytarabine (e.g. arabinosylcytosine (Ara-C), e.g. Cytosar-U®),cytarabine liposomal (e.g. Liposomal Ara-C, e.g. DepoCyt™), decitabine(e.g. Dacogen®), hydroxyurea (e.g. Hydrea®, Droxia™ and Mylocel™),fludarabine (e.g. Fludara®), floxuridine (e.g. FUDR®), cladribine (e.g.2-chlorodeoxyadenosine (2-CdA) e.g. Leustatin™), methotrexate (e.g.amethopterin, methotrexate sodim (MTX), e.g. Rheumatrex® and Trexall™),pentostatin (e.g. Nipent®); Bisphosphonates: Pamidronate (e.g. Aredia®),zoledronic acid (e.g. Zometa®); Demethylating agents: 5-azacitidine(e.g. Vidaza®), decitabine (e.g. Dacogen®); Plant Alkaloids: Paclitaxelprotein-bound (e.g. Abraxane®), vinblastine (e.g. vinblastine sulfate,vincaleukoblastine and VLB, e.g. Alkaban-AQ® and Velban®), vincristine(e.g. vincristine sulfate, LCR, and VCR, e.g. Oncovin® and VincasarPfs®), vinorelbine (e.g. Navelbine®), paclitaxel (e.g. Taxol andOnxal™); Retinoids: Alitretinoin (e.g. Panretin®), tretinoin (all-transretinoic acid, e.g. ATRA, e.g. Vesanoid®), Isotretinoin (13-cis-retinoicacid, e.g. Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®,Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (e.g.Targretin®); Glucocorticosteroids: Hydrocortisone (e.g. cortisone,hydrocortisone sodium succinate, hydrocortisone sodium phosphate, ande.g. Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, HydrocortAcetate® and Lanacort®), dexamethasone, prednisolone (e.g.Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (e.g.Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone(e.g. 6-Methylprednisolone, Methylprednisolone Acetate,Methylprednisolone Sodium Succinate, e.g. Duralone®, Medralone®,Medrol®, M-Prednisol® and Solu-Medrol®); Cytokines: interleukin-2 (e.g.aldesleukin and IL-2, e.g. Proleukin®), interleukin-I 1 (e.g.oprevelkin, e.g. Neumega®), alpha interferon alfa (e.g. IFN-alpha, e.g.Intron® A, and Roferon-A®); Lutinizing hormone releasing hormone (LHRH)agonists: Goserelin (e.g. Zoladex®); Progesterones: megestrol (e.g.megestrol acetate, e.g. Megace®); Miscellaneous cytotoxic agents:Arsenic trioxide (e.g. Trisenox®), asparaginase (e.g. L-asparaginase,Erwinia L-asparaginase, e.g. Elspar® and Kidrolase®); Anti-nausea drugs:NK-1 receptor antagonists: Casopitant (e.g. Rezonic® and Zunrisa® byGlaxoSmithKline); and Cytoprotective agents: Amifostine (e.g. Ethyol®),leucovorin (e.g. calcium leucovorin, citrovorum factor and folinicacid).

Biological Assays

Compounds designed, selected and/or optimised by methods describedabove, once produced, can be characterised using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterised by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

In some embodiments, high-throughput screening can be used to speed upanalysis using such assays. As a result, it can be possible to rapidlyscreen the molecules described herein for activity, using techniquesknown in the art. General methodologies for performing high-throughputscreening are described, for example, in Devlin (1998) High ThroughputScreening, Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughputassays can use one or more different assay techniques including, but notlimited to, those described below.

Various in vitro or in vivo biological assays may be suitable fordetecting the effect of the compounds of the present disclosure. Thesein vitro or in vivo biological assays can include, but are not limitedto, enzymatic activity assays, electrophoretic mobility shift assays,reporter gene assays, in vitro cell viability assays, and the assaysdescribed herein.

Potent Inhibition

Compounds and compositions of the disclosure are potent inhibitors ofone or more oncogenic variants of an EGFR. In some embodiments,compounds and compositions of the disclosure are potent inhibitors ofone or more of a wild type HER-2 receptor or an oncogenic variant of aHER-2 receptor. In some embodiments, the oncogenic variant of a HER-2receptor is an allosteric variant of a HER-2 receptor.

Tables A and B assign each compound a potency code: A, B, C, D, E, F, G,H, I, J or K. According to the code, A represents an IC50 value ≤5 nM. Brepresents an IC50 value >5 nM and ≤510 WM C represents an IC50value >10 nM and ≤20 WM D represents an IC50 value >20 nM and ≤30 nM. Erepresents an IC50 value >30 nM and ≤50 nM. F represents an IC50value >50 nM and ≤100 WM G represents an IC50 value >100 nM and ≤200 WMH represents an IC50 value >200 nM and ≤300 nM. I represents an IC50value >300 nM and ≤5500 nM. J represents an IC50 value >500 nM and 51000nM. K represents an IC50 value >1000 nM.

TABLE A Activity for Inhibiting EGFR Compound No. EGFR WT EGFR V3 EGFRNPH EGFR SVD 1 K G 2 K F 3 I E 4 H F 5 E C E C 6 H D 7 K G 8 I D E D 9 JF 10 K F 11 I F I I 12 J G 13 I F I H 14 I E 15 I H 16 H D 17 H C D C 18I D 19 H D G G 20 H D C C 21 J D C C 22 F D D C 23 K G 24 K H 25 J H D E26 I E E E 27 I E 28 H C F E 29 I D 30 I E 31 J E F F 32 I D 33 I D F F34 J E 35 I D F D 36 K E F F 37 K G 38 I E 39 J D F E 40 H C C C 41 J EF E 42 J F K J 43 K G 44 I G 45 J H 46 I F 47 I E J J 48 K H 49 K G 50 KE 51 J D F E 52 J D F F 53 K E 54 K C G F 55 K F 56 I D I I 57 J C F E58 K H 59 I E 60 H C H H 61 K I 62 I C E D 63 K F I I 64 K G 65 J D 66 JD G F 67 G D 68 J G J J 69 I C D D 70 F C F E 71 J F 72 K I 73 J F 74 KF 75 K G 76 H F 77 G F 78 K E I H 79 I F 80 G F 81 H G 82 J I 83 J F 84J D F F 85 H D D D 86 J G 87 K G 88 J E 89 F E 90 J E 91 J F 92 G E 93 KH 94 I E 95 G D 96 G C 97 J F 98 H E 99 H D 100 I E 101 G C 102 J E F E103 H E 104 D E 105 J F 106 G E 107 H F 108 J G 109 E C 110 H D 111 I E112 I G 113 J F 114 I E 115 H E 116 J E 117 J G 118 H D 119 I F 120 K E121 K G 122 J F 123 H E 124 J E 125 J G 126 I E 127 J F 128 J G 129 J G130 H G 131 H G 132 K I 133 H G 134 H F 135 I F 136 G G 137 H F 138 G F139 J G 140 I G 141 G G 142 J G 143 H F 144 G G 145 G F 146 F F 147 J F148 H G 149 G F 150 H F 151 G F 152 G E 153 J E 154 J E 155 I E 156 K F157 J E 158 G E 159 I G 160 I G 161 H E 162 I E 163 K F 164 I F 165 G E166 K E 167 K E 168 H E 169 K E 170 H E 171 K F 172 J G 173 K F 174 K F175 K E 176 K E 177 J E 178 K E 179 J E 180 J E

TABLE B Activity for Inhibiting HER2 Compound No. HER2 WT HER2 S310FHER2 YVMA 1 F J 2 G I 3 C D 4 D F 5 A A B 6 B C F 7 G H 8 B C F 9 C G 10C D H 11 E F 12 F G 13 B E I 14 C F 15 C G 16 A D E 17 A B E 18 B D F 19B D G 20 A C C 21 A B D 22 A B E 23 G G 24 H I 25 C C F 26 B B E 27 C DE 28 B C E 29 A C F 30 A C G 31 B E G 32 A C F 33 B C G 34 C C F 35 A CE 36 C D E 37 F F 38 B D F 39 B C F 40 A C D 41 B D F 42 E F J 43 F G 44F I 45 I K 46 D G 47 C E J 48 G I 49 F G 50 H K 51 B C F 52 B D G 53 E G54 B D G 55 F H 56 D F H 57 B C F 58 G I 59 E G 60 B D I 61 I K 62 A B E63 E F I 64 I K 65 C C F 66 F C F 67 B C F 68 C E I 69 C D 70 B B 71 H K72 I K 73 E I 74 G H 75 G I 76 E G 77 D G 78 C F J 79 G K 80 F J 81 G K82 F J 83 C G 84 B E 85 B E 86 D G 87 E H 88 C G 89 C F 90 D G 91 E H 92D G 93 J K 94 E I 95 B E 96 C H 97 H J 98 D H 99 E H 100 F I 101 C E 102D F 103 C F 104 E E 105 E G 106 E G 107 C E 108 F J 109 C F 110 E H 111E G 112 I K 113 E G 114 E G 115 E F 116 E H 117 F G 118 C D 119 F G 120C F 121 E I 122 G J 123 E G 124 E G 125 G K 126 E F 127 I K 128 G I 129E G 130 E I 131 F I 132 I J 133 F J 134 E I 135 G I 136 E G 137 F I 138E F 139 E G 140 G I 141 E I 142 I K 143 E G 144 E G 145 E H 146 D F 147F H 148 D F 149 C E 150 C E 151 C G 152 B F 153 C F 154 E G 155 C E 156E H 157 E I 158 E G 159 F I 160 G I 161 E G 162 E G 163 E G 164 E G 165C F 166 E G 167 C F 168 D F 169 C E 170 B C 171 F I 172 F I 173 E H 174F I 175 D G 176 D G 177 C F 178 E G 179 C E 180 D G

In some embodiments, the compound is capable of inhibiting a mutant EGFR(e.g., EGFR-Viii, EGFR-NPH, or EGFR-SVD).

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless, 80 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, or 5 nM or less for inhibiting amutant EGFR (e.g., EGFR-Viii, EGFR-NPH, or EGFR-SVD).

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless for inhibiting EGFR-Viii. In some embodiments, the compound isselected from the group consisting of 2, 3, 4, 5, 6, 8, 9, 10, 11, 13,14, 16, 17, 18, 19, 20, 21, 22, 2627, 28, 29, 30, 31, 32, 33, 34, 35,36, 38, 39, 40, 41, 42, 46, 47, 50, 51, 52, 53, 54, 55, 56, 57, 59, 60,62, 63, 65, 66, 67, 69, 70, 71, 73, 74, 76, 77, 78, 79, 80, 83, 84, 85,88, 115, 116, 118, 119, 120, 122, 123, 124, 126, 127, 134, 135, 137,138, 143, 145, 146, 147, 149, 150, 151, 152, 153, 154, 155, 156, 157,158, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174,175, 176, 177, 178, 179, 180, and pharmaceutically acceptable salts andstereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 50 nM orless for inhibiting EGFR-Viii. In some embodiments, the compound isselected from the group consisting of 3, 5, 6, 8, 14, 16, 17, 18, 19,20, 21, 22, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41,47, 50, 51, 52, 53, 54, 56, 57, 59, 60, 62, 65, 66, 67, 69, 70, 78, 84,85, 88, 115, 116, 118, 120, 123, 124, 126, 152, 153, 154, 155, 157, 158,161, 162, 165, 166, 167, 168, 169, 170, 175, 176, 177, 178, 179, 180,and pharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 30 nM orless for inhibiting EGFR-Viii. In some embodiments, the compound isselected from the group consisting of 5, 6, 8, 16, 17, 18, 19, 20, 22,28, 29, 32, 33, 35, 39, 40, 51, 52, 54, 56, 57, 60, 62, 65, 66, 67, 69,70, 84, 85, 118, and pharmaceutically acceptable salts and stereoisomersthereof.

In some embodiments, the compound exhibits an IC₅₀ value of 20 nM orless for inhibiting EGFR-Viii. In some embodiments, the compound isselected from the group consisting of 5, 17, 28, 40, 54, 57, 60, 62, 69,70, and pharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits greater inhibition of amutant EGFR (e.g., EGFR-Viii, EGFR-NPH, or EGFR-SVD) relative towild-type EGFR.

In some embodiments, the compound exhibits at least 2-fold, 3-fold,5-fold, 10-fold, 20-fold, 30-fold, 50-fold, or 100-fold greaterinhibition of a mutant EGFR (e.g., EGFR-Viii, EGFR-NPH, or EGFR-SVD)relative to wild-type EGFR.

In some embodiments, the compound exhibits at least 5-fold greaterinhibition of EGFR-Viii relative to wild-type EGFR. In some embodiments,the compound is selected from the group consisting of 1, 2, 3, 6, 7, 8,9, 10, 12, 14, 16, 17, 18, 19, 20, 21, 23, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 49, 50, 51, 52, 53, 54,55, 56, 59, 60, 62, 63, 64, 65, 66, 68, 69, 70, 71, 73, 74, 75, 78, 79,83, 84, 85, 86, 87, 88, 115, 116, 117, 118, 120, 121, 122, 123, 124,125, 126, 127, 128, 129, 135, 139, 147, 153, 154, 155, 156, 157, 158,161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,177, 178, 179, 180, and pharmaceutically acceptable salts andstereoisomers thereof.

In some embodiments, the compound exhibits at least 10-fold greaterinhibition of EGFR-Viii relative to wild-type EGFR. In some embodiments,the compound is selected from the group consisting of 2, 3, 6, 8, 10,16, 17, 18, 21, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40,41, 42, 47, 50, 51, 52, 53, 54, 55, 56, 57, 59, 60, 62, 63, 65, 66, 69,73, 74, 78, 83, 84, 85, 88, 116, 118, 120, 122, 124, 126, 147, 153, 154,156, 157, 163, 167, 169, 171, 173, 174, 175, 176, 177, 178, 179, 180,and pharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits at least 20-fold greaterinhibition of EGFR-Viii relative to wild-type EGFR. In some embodiments,the compound is selected from the group consisting of 8, 34, 36, 39, 41,50, 51, 52, 53, 54, 57, 65, 66, 69, 78, 84, 88, 120, 153, 169, 175, 176,178, 179, and pharmaceutically acceptable salts and stereoisomersthereof.

In some embodiments, the compound exhibits at least 30-fold greaterinhibition of EGFR-Viii relative to wild-type EGFR. In some embodiments,the compound is selected from the group consisting of 51, 53, 54, 65,66, 78, 84, 120, and pharmaceutically acceptable salts and stereoisomersthereof.

In some embodiments, the compound is capable of inhibiting wild-typeHER2 or a mutant HER2 (e.g., HER2-S310F or HER2-YVMA).

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless, 80 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, or 5 nM or less for inhibitingwild-type HER2 or a mutant HER2 (e.g., HER2-S310F or HER2-YVMA).

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless, 80 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, or 5 nM or less for inhibitingwild-type HER2.

In some embodiments, the compound exhibits an IC_(m) value of 50 nM orless for inhibiting wild-type HER2. In some embodiments, the compound isselected from the group consisting of 3, 4, 5, 6, 8, 9, 10, 11, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 38, 39, 40, 41, 42, 46, 47, 51, 52, 54, 56, 57, 59, 60, 62, 63,65, 67, 68, 78, 81, and pharmaceutically acceptable salts andstereoisomers thereof.

In some embodiments, the compound exhibits an IC_(m) value of 20 nM orless for inhibiting wild-type HER2. In some embodiments, the compound isselected from the group consisting of 3, 5, 6, 8, 9, 10, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,38, 39, 40, 41, 47, 51, 52, 54, 57, 60, 62, 65, 67, 68, 78, andpharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 10 nM orless for inhibiting wild-type HER2. In some embodiments, the compound isselected from the group consisting of 5, 6, 8, 16, 17, 18, 19, 20, 21,22, 26, 28, 29, 30, 31, 32, 33, 35, 38, 39, 40, 41, 51, 52, 54, 57, 60,62, 67, and pharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 5 nM or lessfor inhibiting wild-type HER2. In some embodiments, the compound isselected from the group consisting of 5, 16, 17, 21, 22, 29, 30, 32, 35,62, and pharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless, 80 μM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, or 5 nM or less for inhibiting amutant HER2 (e.g., HER2-S310F or HER2-YVMA).

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless for inhibiting HER2-S310F. In some embodiments, the compound isselected from the group consisting of 3, 4, 5, 6, 8, 10, 11, 13, 14, 16,17, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 47, 51, 52, 53, 54, 56, 57, 60, 62, 63, 65, 66,67, 68, 69, 70, 73, 76, 77, 78, 82, 83, 84, 85, 86, 87, 88, 115, 116,117, 118, 119, 120, 121, 123, 124, 126, 129, 130, 131, 133, 134, 136,137, 138, 139, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152,153, 154, 155, 156, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167,168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, andpharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 50 nM orless for inhibiting HER2-S310F. In some embodiments, the compound isselected from the group consisting of 3, 4, 5, 6, 8, 10, 13, 16, 17, 18,19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39,40, 41, 47, 51, 52, 53, 54, 57, 60, 62, 65, 66, 67, 68, 69, 70, 73, 76,77, 83, 84, 85, 86, 87, 88, 115, 116, 118, 120, 121, 123, 124, 126, 129,130, 134, 136, 138, 139, 141, 143, 144, 145, 146, 148, 149, 150, 151,152, 153, 154, 155, 156, 157, 158, 161, 162, 163, 164, 165, 166, 167,168, 169, 170, 173, 175, 176, 177, 178, 179, 180, and pharmaceuticallyacceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 20 nM orless for inhibiting HER2-S310F. In some embodiments, the compound isselected from the group consisting of 5, 6, 8, 17, 20, 21, 22, 25, 26,28, 29, 30, 32, 33, 34, 35, 39, 40, 51, 57, 62, 65, 66, 67, 69, 70, 83,84, 85, 88, 118, 120, 149, 150, 151, 152, 153, 155, 165, 167, 169, 170,177, 179, and pharmaceutically acceptable salts and stereoisomersthereof.

In some embodiments, the compound exhibits an IC₅₀ value of 10 nM orless for inhibiting HER2-S310F. In some embodiments, the compound isselected from the group consisting of 5, 17, 21, 22, 62, 70, 84, 85,152, 170, and pharmaceutically acceptable salts and stereoisomersthereof.

In some embodiments, the compound exhibits an IC₅₀ value of 100 nM orless for inhibiting HER2-YVMA. In some embodiments, the compound isselected from the group consisting of 5, 6, 8, 16, 17, 18, 20, 21, 22,25, 26, 27, 28, 29, 32, 34, 35, 36, 38, 39, 40, 41, 57, 62, 65, 66, 67,69, 70, 84, 85, 115, 118, 120, 126, 138, 146, 148, 149, 150, 152, 153,155, 165, 167, 168, 169, 170, 177, 179, and pharmaceutically acceptablesalts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 50 nM orless for inhibiting HER2-YVMA. In some embodiments, the compound isselected from the group consisting of 5, 16, 17, 20, 21, 26, 27, 28, 35,36, 40, 41, 62, 69, 70, 84, 85, 118, 149, 150, 155, 169, 170, 179, andpharmaceutically acceptable salts and stereoisomers thereof.

In some embodiments, the compound exhibits an IC₅₀ value of 30 nM orless for inhibiting HER2-YVMA. In some embodiments, the compound isselected from the group consisting of 5, 20, 21, 26, 40, 69, 70, 118,170, and pharmaceutically acceptable salts and stereoisomers thereof.

Paradoxic ErbB Receptor Activation

Although the mechanisms described herein apply to any form of cancer inwhich these EGFR variants of the disclosure are expressed, theprevalence of these variants in glioblastoma (GBM) are provide by way ofexample. Other cancers expressing the EGFR variants of the disclosureinclude, but are not limited to, solid cancers, epithelial cancersand/or cancers of epithelial origin, bladder cancer, breast cancer,cervical cancer, colorectal cancer, endometrial cancer, gastric cancer,glioblastoma (GBM), head and neck cancer, lung cancer, and non-smallcell lung cancer (NSCLC).

In GBM tumors EGFR is frequently the target of genomic mutations andalternative splicing events that result in alteration of theextracellular dimer interface. Many tumors express more than oneaberrant isoform. The disclosure provides the mechanism of activationfor the most commonly occurring variants, EGFR-Viii, EGFR-Vii, EGFR-Vvi,and EGFR-A289V. Although each isoform is the result of a distinctectodomain alteration, all are activated by a common mechanism involvingcovalent ligand-independent dimerization.

AMG-595 (Amgen) is an EGFR-Viii isoform selective antibody that has noactivity against wild type EGFR or other splice-activated variants.Rindopepimut (Celldex) is a vaccine the produces an immunologicalresponse selectively against tumor cells expressing EGFR-Viii but notwild type EGFR or other splice-activated isoforms. Other EGFR isoformsexpressed in GBM tumors (EGFR-Vii and EGFR-Vvi) are constitutivelyactive covalent receptors and their expression may limit the breadth andduration of treatment benefit for an ErbB inhibitor that is selectiveonly for EGFR-Viii. Therefore, it may be useful to exclude patientswhose tumors express EGFR-Vii, EGFR-Vvi, or EGFR ectodomain pointmutants from treatment with an EGFR-Viii selective therapy.

The heterogenenic expression pattern for multiple ectodomain variants ofErbB receptors in tumors indicates that a small molecule inhibitor thatinhibits all variants is preferred. The family of covalently-activatedEGFR isoforms responds very differently to small molecule ErbBinhibitors compared to EGFR catalytic domain mutations observed inNSCLC. Importantly, Type I inhibitors, including erlotinib, all inducethe formation of covalent EGFR dimers and increase EGFR phosphorylationat sub-saturating concentrations, an activity that is further enhancedwhen ErbB inhibitor is washed away. This manifests in paradoxicalactivation of proliferation at sub-saturating concentrations.

The discovery of paradoxical activation of proliferation atsub-saturating concentrations of Type I ErbB inhibitors is furtherdemonstrated for a series of extracellular variants of HER2, prevalentin a number of cancers including breast and bladder. All variantsexisted as covalently activated receptors, and levels of covalent dimersincreased following treatment with Type I inhibitors including sapitiniband afatinib. As with covalently-activated EGFR variants, sub-saturatingdoses of Type I inhibitors increased phosphorylation of HER2 variants,increasing the proliferation of cells expressing them.

In contrast to Type I inhibitors, the disclosure demonstrates thatNon-Type I (e.g. Type II) inhibitors, including neratinib, are devoid ofparadoxical activation for cells expressing ErbB ectodomain variants.Neratinib is found to exemplify a molecule that is both potent andselective for each member of the covalently-activated EGFR family versuswild type EGFR.

In some embodiments, the disclosure provides a structure/functionalrelationship for predicting how structural variations affecting receptorregions distal to the active site can confer different responses tosmall molecule active site inhibitors. The disclosure described hereinof paradoxical activation of covalently-activated ErbB receptor variantsby Type I inhibitors has important clinical implications. The data ofthe disclosure provide a mechanistic explanation for the failed clinicalstudies for Type I inhibitors in tumor types where expression ofcovalently-activated ErbB receptors is prevalent. This includeserlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, andsapitinib in breast tumors. Thus, the disclosure provides methods ofusing tumor expression levels for covalently-activated ErbB receptors asexclusion criteria for treating patients with a Type I ErbB receptorinhibitor therapeutic.

Glioblastoma

Glioblastoma (GBM), grade IV astrocytoma, is the most common form ofbrain cancer. The outcome for this disease is dismal. Surgery followedby a therapeutic regimen of radiation and temozolomide is standard ofcare, however this produces a median overall survival (OS) of only 14.6months and few patients survive for five years. There has been littleprogress made in extending survival for GBM patients over the pastdecade. Although bevacizumab showed an improved progression freesurvival benefit in the recurrent setting, the addition of bevacizumabto standard of care therapy in the front-line setting did not result inan OS benefit.

EGFR is the most frequently altered oncogene in GBM. In addition to EGFRgene amplification, many tumors express variants generated by aberrantsplicing or genomic mutation. The first recognized variant is EGFR-Viii,resulting from truncation of exons 2-7 and expressed by approximately30% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutivelyactivated in the absence of EGF ligand, exhibiting sustained signalingthat is resistant to downregulation. Therefore, EGFR-Viii is bothtransforming and tumorigenic. Expression of EGFR-Viii is associated withpoor long term overall survival in GBM.

RNA sequencing data has revealed that EGFR-Viii is just one of severalaberrantly spliced variants of EGFR expressed in GBM tumors. Two othersresult in truncation of exons 12-13 and 14-15 (EGFR-Vii). LikeEGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition tosplice variants, GBM tumors also express a collection of EGFR pointmutations including C620Y and A289V, which are transforming andtumorigenic. The complex landscape of EGFR alterations in GBM is furthercompounded by the observation that many tumors express more than onereceptor variant.

Because the expression of multiple EGFR variants in GBM gives rise totransforming and tumorigenic activity and because EGFR is the mostfrequently altered oncogene present in GBM tumors, EGFR is an especiallyattractive target for small molecule ErbB inhibitors. Following thesuccess for small molecule EGFR therapeutics against NSCLC tumorsharboring activating mutations in EGFR (erlotinib, gefitinib, andafatinib), these drugs were tested in GBM. Despite intense clinicalinvestigation of this group of ErbB inhibitors in GBM, involving >30clinical trials and >1500 patients, all failed to produce any benefit,even for those tumors that expressed EGFR-Viii. Some evidence suggeststhat erlotinib promoted disease progression. A phase II study evaluatingerlotinib in combination with radiation and temozolomide showed medianPFS (mPFS) and median OS (mOS) of 2.8 months and 8.6 months, as comparedto 6.9 months and 14.6 months for patients receiving radiation andtemozolomide alone. Another randomized phase II trial with erlotinibshowed that patients who received erlotinib, including those whosetumors expressed EGFR-Viii, performed worse by a number of parametersthan those patients who received standard of care therapy. The clinicalfailures for ErbB inhibitors such as erlotinib in GBM tumors has castdoubt on the role of EGFR as a driver of tumor growth in GBM and led toinquiry as to why ErbB inhibitors that were so effective in treatingEGFR mutations in lung cancer were so ineffective in treating EGFRvariants in GBM.

A feature for the EGFR variants expressed in GBM is their locationwithin the extracellular domain. This is in contrast to activatingmutations of EGFR found in lung cancer, which often reside in theintracellular catalytic domain. EGFR is composed of four extracellulardomains (two ligand binding domains and two cysteine rich regions), atransmembrane domain, and an intracellular catalytic domain. Ligandbinding promotes dimerization of the extracellular cysteine rich domains(CR1 and CR2), an event that confers dimerization of the intracellulardomain and activation of receptor catalytic activity. Nearly all EGFRsplicing events and mutations in GBM affect the extracellular region,including two cysteine rich regions (CR1 and CR2) that form theextracellular dimer interface. The CR regions contain >40 cysteineresidues, all of which form intramolecular disulfide bonds. InEGFR-Viii, truncation of exons 2-7 results in partial loss of sequenceencoding the CR1 region. A consequence is loss of one cysteine from theCys295-Cys307 pair, leaving Cys307 as a free unpaired cysteine. ForEGFR-Viii, this cysteine can form an intermolecular disulfide bond withanother EGFR monomer to drive a covalently dimerized and constitutivelyactivated receptor. Mutation of Cysteine 307 to a Serine (C307S)prevents the formation of covalently dimerized EGFR-Viii and isinactive.

Although several recent preclinical studies have suggested that EGFRkinase inhibitors such as erlotinib are ineffective at inhibitingEGFR-Viii, there has been no mechanism proposed for this effect. Thereis also a lack in current understanding for the mechanism responsiblefor activation of other ectodomain variants in GBM, including EGFR-Viiand EGFR-A289V. The disclosure provides a mechanism of receptoractivation and impact on ErbB inhibitor activity for a group of four ofthe most common ectodomain variants in GBM, EGFR-Viii, EGFR-Vii,EGFR-delta 12-13, and EGFR-A289V.

The disclosure demonstrates that like EGFR-Viii, an additional group ofcommonly occurring EGFR variants in GBM (EGFR-Vii, EGFR-Vvi, andEGFR-A289V) all exist as constitutively active covalent dimers andtogether form a family of EGFR isoforms that are activated by thiscommon mechanism. In some embodiments, the disclosure shows that thepropensity of these variants to covalently dimerize is coupled to theconformation of the intracellular catalytic site, conferring distinctactivity for classes of small molecules inhibitors binding to thisdistal site. Inhibitors that stabilize the active conformation of thekinase (Type I inhibitors, including erlotinib) induce the formation ofcovalent dimers for all covalently-activated EGFR isoforms. This isassociated with the propensity of Type I inhibitors to increase EGFRphosphorylation at sub-saturating concentrations and to paradoxicallystimulate the proliferation of cells expressing covalently-activatedEGFR isoforms.

Neither enhanced dimerization nor paradoxical activation of EGFR is seenwith small molecule inhibitors that stabilize the inactive kinaseconformation (Type II inhibitors, including lapatinib and neratinib).Examples of Type II inhibitors were identified that were potentinhibitors of covalently-activated EGFR isoforms and which wereselective for this family compared to WT-EGFR.

Similar to the mutations identified for EGFR, the disclosure identifiesa group of splice events and mutations affecting the CR domains of HER2and HER4. The disclosure demonstrates that this group of splice eventsand mutations affecting the CR domains of HER2 and HER4 exists ascovalent dimers and are paradoxically activated by agents with a Type Ibinding mode. These data provide a mechanistic explanation for thefailure of multiple clinical trials involving Type I inhibitors,including >30 clinical trials of Type I ErbB inhibitors in GBM.Collectively these data indicate that tumors expressingcovalently-activated EGFR isoforms should be excluded from treatmentwith Type I ErbB inhibitors such as erlotinib because of paradoxicalactivation. These data further demonstrate the utility for optimizingType II ErbB inhibitors against the covalently-activated ErbB family.

Clinical Trials Using Type I ErbB Inhibitors

Methods of the disclosure identify subjects expressing ErbB familyreceptor variants in one or more cancer cells or cancer cell types ofthe subject. Identification of a subject as having a variant of thedisclosure may be used as either inclusion or exclusion criteria foreither a clinical trial to assess the efficacy of an existing or novelcancer treatment or for an approved treatment protocol.

In some embodiments, the methods of the disclosure may be used toexclude patients expressing one or more of the ErbB variants of thedisclosure from a clinical trial assessing the safety and/or efficacy ofa Type I inhibitor of the disclosure. The ErbB variants of thedisclosure are paradoxically activated upon contact with a Type Iinhibitor, leading to increased proliferation of the cancer cell. Inpast and ongoing clinical trials, the patient populations used for thesestudies had not been screened for expression of an ErbB variant of thedisclosure. Consequently, a Type I inhibitor of the disclosure that“failed” a clinical trial by failing to show increased efficacy over astandard treatment or placebo for the treatment of cancer may, in fact,be effective but the results may have been confounded by the inclusionof patients who express an ErbB variant of the disclosure. Becausepatients who express an ErbB variant of the disclosure may demonstrateincreased proliferation of cancer cells when treated with a Type Iinhibitor, and, therefore, demonstrate a lack of improvement or even afurther progression of the cancer, these patients may prevent approvalof cancer therapeutics that could be life-saving for those patients whodo not express an ErbB receptor variant of the disclosure. Thus, themethods of the disclosure include identifying a subject as expressing anErbB receptor variant of the disclosure and excluding this patient fromtreatment with a Type I inhibitor. In some embodiments, a patient whoexpresses an ErbB receptor variant of the disclosure may be treated witha Non-Type I inhibitor, including a Type II inhibitor.

In some embodiments, when a patient who expresses an ErbB receptorvariant of the disclosure is identified as expressing only the EGFR-Viiisplice variant, the patient may be treated with an EGFR-Viii selectiveinhibitor or may be included in a clinical trial for an EGFR-Viiiselective inhibitor. In some embodiment of the methods of thedisclosure, the patient should express only the EGFR-Viii splice variantto be treated with an EGFR-Viii selective inhibitor. If the patientexpresses multiple variants, including the EGFR-Viii variant, resultingin a combination of expressed variants, the patient should be excludedfrom treatment with an EGFR-Viii selective inhibitor, however, thispatient may be successfully treated with a Non-Type I selectiveinhibitor (e.g. a Type II inhibitor).

By extension, should a selective inhibitor target any one or more of theErbB receptor variants of the disclosure, the identification ofexpression of the splice variant in a patient may be used as aninclusion criterion for a clinical study or treatment regimen providingthat selective inhibitor.

Table 1 provides a listing of exemplary clinical trials for Type Iinhibitors that “failed” when in tumor types that express covalentlyactivated ErbB receptors were included in the study. The disclosureprovides a method of screening or re-screening participants in aclinical trial for expression of one or more covalently activated ErbBreceptor variants of the disclosure. As a further step, the methods ofthe disclosure include treating those patients who do not express one ormore covalently activated ErbB receptor variants of the disclosure for afirst or subsequent attempt with a Type I inhibitor to determineefficacy of the Type I inhibitor in a tumor type or patient that doesnot express one or more covalently activated ErbB receptor variants ofthe disclosure. In some embodiments, those patients who are excludedfrom a first or subsequent treatment with a Type I inhibitor may betreated with a Non-Type I inhibitor of the disclosure, including a TypeII inhibitor.

TABLE 1 Listing of clinical trials for Type I inhibitors that failed intumor types where expression levels of covalently activated ErbBreceptors is prevalent. Type I inhibitor Tumor Setting Study erlotinibGBM Van den Bent et al. J Clin Oncol., 2009 erlotinib GBM Peereboom etal. J Neuro-oncol., 2010 afatinib GBM Reardon et al. Neuro Oncol., 2014gefitinib SCCHN Argiris et al. J Clin Oncol., 2013 erlotinib SCCHNMartins et al. J Clin Oncol. 2013 gefitinib bladder Petrylak et al. BJUInt. 2010 gefitinib bladder Philips et al. Ann Oncol. 2009 sapitinibbreast NCT00900627/THYME sapitinib breast NCT01151215

Table 2 provides a listing of exemplary ErbB inhibitors of thedisclosure. Methods of the disclosure may include the identification ordetermination of expression of an ErbB receptor of the disclosure aseither an exclusion criteria for treatment or a clinical trialadministering a Type I inhibitor or as inclusion criteria for treatmentor a clinical trial administering a Non-Type I (e.g. Type II) inhibitoror the NT-113 Type I inhibitor.

TABLE 2 Exemplary ErbB inhibitors Inhibitor Name CAS Number Type I?CUDC-101 1012054-59-9 Yes poziotinib (HM781-36B) 1092364-38-9 Yesdacomitinib (PF-299804) 1110813-31-4 Yes JNJ-26483327 1131863-89-2 YesWZ 4002 1213269-23-8 Yes WZ 3146 1214265-56-1 Yes WZ8040 1214265-57-2Yes AP-26113 1350848-43-9 Yes Rociletinib (CO 1686, AVL301) 1374640-70-6Yes NT-113 1398833-56-1 Yes AZD9291 1421373-65-0 Yes erlotinib (OSI-744)183319-69-9 Yes gefitinib (ZD1839) 184475-35-2 Yes PKI 166 187724-61-4Yes PD 168393 194423-15-9 Yes BIBX 1382 196612-93-8 Yes vatalanib(CGP79787) 212141-54-3 Yes lapatinib 231277-92-2 No** pelitinib(EKB-569) 257933-82-7 Yes Canertinib (Cl-1033) 267243-28-7 Yes afatinib(BIBW2992) 439081-18-2 Yes vandetanib (ZD6474) 443913-73-3 Yes AEE788497839-62-0 Yes icotinib (BPI-2009H) 610798-31-7 Yes dovitinib692737-80-7 Yes neratinib (HKI-272) 698387-09-6 No** AC-480 (BMS-599626)714971-09-2 Yes XL-647 781613-23-8 Yes HKI-357 848133-17-5 No**Sapitinib (AZD8931) 848942-61-0 Yes TAK 285 871026-44-7 No** AST 1306897383-62-9 No** AV-412 451493-31-5 Yes * Type I inhibitors of thedisclosure are characterized by their mode of kinase inhibition which isdescribed by their ability to target the ATP-binding site in an activeconformation to competitively inhibit ATP-binding. Key structuralelements have been described including an alignment of specifichydrophobic residues. **Inhibitors of inactive kinases bind to target insuch a manner as to disrupt key structural elements of the activeconformation, including specific hydrophobic residues. These non-Type Iinhibitors are differentiated from Type I inhibitors by theirinteraction with target in such a way as to prevent the target adoptingan active ATP-binding conformation. Non-Type I inhibitors of thedisclosure include, but are not limited to Type II inhibitors.Inhibitors that are not Type I inhibitors in this table are Type IIinhibitors.

Paradoxical Stimulation of Proliferation by Type 1 Inhibitors in CellsDriven by Covalently-Activated ErbB Oncoproteins

Although illustrated through the example of EGFR variants in thediagnosis and treatment of glioblastoma, the methods of the disclosureinclude ErbB receptor variants (e.g. EGFR, and HER2 variants) in anycancer in which these variants are expressed. An exemplary collection ofthese variants is provided in Table 3.

TABLE 3 Exemplary Covalent ErbB Oncoproteins Receptor Event Event TypeRegion Expression EGFR Viii splicing CR1 (deletion of GBM, exons 2-7)NSCLC, SCCNHN EGFR Vii splicing CR2 (deletion of GBM exons 14-15) EGFRVvi splicing CR2 (deletion of GBM exons 12-13) EGFR delta768 splicingCR1 (deletion of neuroblastoma nucleotides 102-769) EGFR delta660splicing CR1 (deletion of SCCHN nucleotide 237 of exon 2 to 896 of exon8) ErbB2 delta16 splicing CR2 (deletion of exon GBM 16) ErbB2 p95HER2splicing/altered AA 1-611 deletion Breast translation start/ proteolyticcleavage

With respect to EGFR and glioblastoma, RNA sequencing of 164 GBM tumorsreveals heterogenous expression of multiple ectodomain variants of EGFR.Aberrant splicing, alone or coincident with genomic rearrangement,produces EGFR-Viii (loss of exons 2-7), EGFR-Vii (loss of exons 14-15),and EGFR-Vvi (loss of exons 12-13), Table 4.

TABLE 4 Tumor expression Exons Free Cys Variant (prevalence) spliced ontPosition generated EGFR-Vii GBM (3%) 14-15 CR2 Cys539, Cys628, Cys636EGFR-Viii GBM (20%)/ 2-7 CR1 Cys307 SCCHN (36%)/ NSCLC (3%)/ BrCa (5%)EGFR-Vvi GBM (32%) 12-13 CR2 Cys555 EGFR-A289V GBM (16%) NA CR1 NDPrevalence is based on expression levels >1% as reported by TCGA datasets (Brennan et al. (2013) Cell 155(2): 462-477).

All three ectodomain variants affect the CR1 or CR2 regions and resultin loss of exons coding for sequence at the extracellular dimerinterface. There is also a series of greater than 20 genomic mutationsfound in GBM tumors, which also map to the CR1 and CR2 regions at thedimer interface (see, for example, FIG. 1 and Table 5).

TABLE 5 Mutation Region R222C CR1 R252C/P CR1 R256Y CR1 T263P CR1 Y270CCR1 A289T/V/D CR1 H304Y CR1 G331R CR1 P596S/L/R CR2 G598V/A CR2 G614DCR2 C628F/Y CR2 C636Y CR2 S645C CR2

The most common of these affect A289, with A289V being most prevalent.EGFR-Viii is expressed by 20%, Vii by 3% and Vvi by 32% of tumors.Mutations within the extracellular region are observed in 40% of tumors,and at position A289 by 16% of tumors. Expression of at least onevariant is observed in 65% of GBM tumors (FIG. 2). Many tumors expressmultiple variants. This is exemplified by TCGA.878, a GBM tumorexpressing EGFR-Viii, A289T, A289V, and A289D (FIG. 2). 69% of tumorsexpressing EGFR-Viii also co-express at least one other ectodomainvariant of EGFR, and several tumors co-expressed all three ectodomainvariants. Only 6% of GBM tumors express EGFR-Viii in isolation.Expression of EGFR in GBM may be mutually exclusive with expression ofother RTK oncogenes, which are co-expressed with EGFR variants in only7% of GBM tumors. These data demonstrate how EGFR alterations in GBMhave a dominant and mutually exclusive expression pattern compared withother oncogenic drivers.

Splicing events and mutations affecting the extracellular ligand bindingdomain have been shown to be both transforming and tumorigenic. The dataof the disclosure confirmed the transforming properties for EGFR-Viii,EGFR-Vii, and EGFR-A289V. When expressed in BaF3 cells all transformedcells to proliferate in the absence of IL-3 (FIG. 3).

The x-ray structure for the ectodomain of wild type EGFR reveals 21intramolecular disulfide bonds lining the dimer interface at the CR1 andCR2 regions. Exemplary disulfide bonds lining the dimer interface at theCR1 and CR2 regions may occur at one or more regions of C190-C199,C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260,C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523,C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617,C620-C628 and C624-C636 according to SEQ ID NO: 1. Similarly, exemplarydisulfide bonds lining the dimer interface at the CR1 and CR2 regions ofa HER-2 receptor may occur at one or more regions of C199-C212,C220-C227, C224-C235, C236-C244, C240-C252, C255-C264, C268-C295,C299-C311, C315-C331, C334-C338, C342-C367, C511-C520, C531-C540,C544-C560, C563-C576, C567-C584, C587-C596, C600-C623, C626-C634 andC630-C642.

This is a common feature for all ErbB receptors. One of the 11intramolecular disulfide bonds in the CR1 region of EGFR is formed byCys295-Cys307, which is disrupted in EGFR-Viii. Loss of sequence codingfor part of the CR1 region eliminates Cys295, leaving Cys307 free toform an intermolecular disulfide bond with another EGFR-Viii monomer(FIG. 4). The mutation Cys307-Ser prevents formation of covalentEGFR-Viii dimers and exhibits reduced tumorigenicity in vivo.

Inspection of sequences losses produced by truncations for both EGFR-Vviand EGFR-Vii reveals that intramolecular disulfide bonds at the CR2ectodomain dimer interface will be disrupted. Loss of exons 14-15 inEGFR-Vvi will result in disruption of the Cys539-Cys555 bond, leavingCys555 as a free cysteine, and loss of exons 14-15 in EGFR-Vii willresult in disruption of the Cys539-Cys555, Cys620-Cys628 andCys624-Cys636 bonds, leaving Cys555, Cys628 and Cys636 as freecysteines. Cys555, Cys628, and Cys636 all reside in the CR2 region ofthe dimerization interface, FIG. 4. Free cysteines generated at thesesites could confer the potential for receptors to form covalent dimers,as has been demonstrated for EGFR-Viii.

Point mutations may reside in cysteine rich regions CR1 and CR2 andcould also affect disulfide bonds at the ectodomain dimer interface(FIG. 1). Some point mutations may introduce new cysteines into the CR1region (e.g. R252C). Other mutations may directly affect cysteines thatform intramolecular disulfide bonds in the CR2 region of wild type EGFR(e.g. C624F), and some of these have been shown to promote covalentlydimerized receptors in the presence of EGF ligand. Many other mutationsdo not directly affect cysteine composition within the ectodomain butare situated in close proximity to native intramolecular disulfide bondsat the dimer interface, and offer the potential to disrupt thesestructures. Indeed mutations that are adjacent to a disulfide bond inthe third Ig-like domain of FGFR2 have been shown to disrupt this bondand confer a covalently dimerized and activated receptor. A289, the mostcommon site for mutation in GBM, is less than 10 angstroms from theCys-295-Cys307 bond, and alterations at this site might disrupt thisdisulfide, resulting in presentation of free cysteines at the CR1 dimerinterface region.

The occurrence of free cysteines at the ectodomain dimer interface forEGFR-Vvi, EGFR-Vii, and EGFR-A289V could give rise to covalent andconstitutively active dimers as has been demonstrated for EGFR-Viii. Totest this hypothesis, each receptor isoform was expressed in U87-MGtumor cells, which endogenously express only a very low level of wildtype EGFR, and evaluated for the phosphorylation of EGFR undernon-reducing conditions to allow detection of covalently dimerizedversus monomeric receptor. EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289Vwere all present as covalent and active receptors (FIG. 5). Althoughcovalent dimer represented only a minor fraction of total receptorlevels, the majority of phosphorylated and activated receptors werepresent as covalent dimers. Therefore, distinct rearrangements withinthe ectodomain generated by genomic alterations and aberrant splicingall produce receptors activated by a common mechanism involving ligandindependent covalent dimerization.

The ability of EGF ligand to modulate the activity for each member ofthe splice-activated EGFR family was assessed. In EGFR-Viii the ligandbinding domain has been mostly truncated because of loss of sequenceencoded by exons 2-7. The addition of EGF has no effect on thephosphorylation of monomeric or covalently dimerized EGFR-Viii expressedin U87-MG cells (FIG. 6). The ectodomain truncations for both EGFR-Viiand EGFR-Vvi occur downstream and affect sequence within the CR2 regionmore proximal to the transmembrane domain. The EGF binding site isintact for both of these variants. In contrast to EGFR-Viii, bothEGFR-Vii and EGFR-Vvi have constitutive basal activity for covalentdimers, which can be further enhanced by EGF (FIG. 6).

The ability of multiple aberrations of EGFR in GBM to drive constitutiveactivation indicates that EGFR is an important therapeutic target.However, none of the ErbB inhibitors approved for treatment of EGFRcatalytic site mutations in NSCLC proved effective in treating GBM. Theexperiments of the disclosure sought to establish whether small moleculeErbB inhibitors that have demonstrated clinical activity againstoncogenic catalytic mutations expressed in NSCLC might have differentialactivity against each of the covalently-activated EGFR isoforms. Herein,the data demonstrate that erlotinib enhances the formation of covalentdimers for all three splice-activated EGFR isoforms and EGFR-A289V (FIG.7A). These effects were dose-dependent (FIG. 7B). This ability oferlotinib to induce covalent dimers for covalently-activated EGFRvariants was observed for all Type I ErbB inhibitors, but not Type IIinhibitors, and includes molecules with either reversible or covalentbinding modes (FIG. 8 and Table 6).

TABLE 6 Molecule Binding Mode Class Induced dimers Erlotinib reversibleType I Yes Gefitinib reversible Type I Yes Lapatinib reversible Type IINo Afatinib covalent Type I Yes CO-1686 covalent Type I Yes AZD9291covalent Type I Yes WZ8040 covalent Type I Yes WZ3146 covalent Type IYes WZ4002 covalent Type I Yes Neratinib covalent Type II No HKI-357covalent Type II No PD168393 covalent Type I Yes Canertinib covalentType I Yes Pelitinib covalent Type I Yes Dacomitinib covalent Type I YesAST-1306 covalent Type II No

This discovery was extended to two other splice variants that wereidentified in glioblastoma and head and neck cancers, EGFR-A768 andEGFR-A660 (FIG. 9 and Table 7). Both receptor isoforms could exist ascovalently activated receptors, and erlotinib induced covalentdimerization for both.

TABLE 7 Tumor expression Exons Free Cys Variant (prevalence) spliced outPosition generated EGFR-Δ768 Neuroblastoma (NA) 2-7 (partial) CR1 Cys291EGFR-Δ660 SCCHN (NA) 2-8 (partial) CR1 Cys 307

Treatment with sub-saturating concentrations of the Type I ErbBinhibitor erlotinib also results in enhanced phosphorylation ofcovalently-activated EGFR variants, shown for EGFR-Vii, EGFR-Viii, andEGFR-A289V (FIG. 10A). Further, when cells expressing either EGFR-Vii orEGFR-Vvi are treated with erlotinib, and then washed prior to collectionof lysates, all show enhanced phosphorylation compared to untreatedcontrol cells, consistent with increased dimer formation in response tothe Type I inhibitor (FIG. 10B).

To assess the impact of enhanced EGFR activity evoked by sub-saturatingconcentrations of erlotinib on cell proliferation, EGFR-Viii, EGFR-Vii,and EGFR-A289V were expressed in BaF3 cells to transform them to IL-3independence. While high saturating concentrations of erlotinib (1 uM)inhibited proliferation of BaF3-EGFR-Viii cells, lower sub-saturatingconcentrations (37 nM) stimulated proliferation (FIG. 11A). The biphasiceffect of erlotinib on the proliferation of cells expressingcovalently-activated EGFR was similarly seen in BaF3 cells expressingEGFR-Vii or EGFR-A2989V, but was not seen in isogenic BaF3 cellsexpressing the oncogenic EGFR catalytic domain mutation E746-A750 (FIG.11B), thus demonstrating that paradoxical activation is specific tocovalently-activated EGFR isoforms. The biphasic effect on proliferationfor cells expressing EGFR-Viii was also seen with the covalentinhibitors WZ8040, WZ4002, and WZ3146, indicating that this behaviorexists for small molecules with both reversible and covalent bindingmodes (FIG. 12). The ability of Type I inhibitors to paradoxicallyenhance cell proliferation at sub-saturating drug concentrations isfully consistent with the ability of molecules with this type ofmechanism to promote the formation of covalently activated dimers.

Mutations and splicing events affecting the CR1 and CR2 regions of theHER2 and HER4 ectodomains are also observed cancer (Table 8). The mostcommon of these is HER2Δ16, expressed in approximately 50% of breastcancers, but not detected in any normal tissue. HER2Δ16 results fromalternative splicing and loss of exon 16, encoding the extracellularjuxtamembrane region, producing two free cysteine residues situated atthe dimer interface in the CR2 region, Cys626 and Cys630 (Table 8).Compared to HER2-WT, HER2Δ16 is highly tumorigenic. In breast cancerpatients, expression of HER2Δ16 is associated with greater incidence oflymph node involvement and metastatic disease.

TABLE 8 Tumor expression Exons Free Cys Variant (prevalence) spliced outPosition generated HEK2-Δ16 BrCa (52% of 16 CR2 Cys626, HER2+)/GaCaCys630 HER2- GBM (<1%) NA CR1 Cys299 C311R HER2- Bladder (5%), Breast NACR1 ND S310F/Y (2%), Cervical (1%), Stomach (1%), NSCLC (2% squamous)

As observed with EGFR, point mutations also occur at the dimer interfaceof the HER2 CR1 region (Table 8 and FIG. 13). Some mutations introducenovel cysteines or remove one member of a pair of cysteines coordinatingan intramolecular disulfide bond. Other mutations, includingHER2-S310F/Y, are situated proximal to disulfide bonds and mayallosterically disrupt them, as discovered for EGFR-A289V. HER2-S310F/Ymutations are the most frequently occurring HER2 mutations in cancer,expressed by >15% of bladder cancers.

Select extracellular variants of HER2, including HER2-C311R and HER2Δ16,exist as covalently activated dimers. The data of the disclosuredemonstrate that other commonly occurring extracellular variantsincluding HER2-S310F also exist as covalently activated receptors (FIG.14).

Similar to observations for covalently-activated EGFR variants, Type Iinhibitors (sapitinib and afatinib) induce the expression of covalentdimers for HER2 extracellular variants (FIG. 15A). These effects weredose dependent (FIG. 15B). Finally, sapitinib can paradoxicallystimulate the proliferation of BaF3 cells driven by HER2-Δ16 (FIG. 16).Collectively, these data provide instructive guidelines for thetreatment of tumors expressing covalently activated ErbB receptors,including exclusion criteria for Type I inhibitors and preferred methodof treatment for Type II pharmacophores in tumors expressing thesevariant receptors.

Methods

Retroviral Production: EGFR mutants were subcloned intopMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, Calif.).Retroviral expression vector retrovirus was produced by transienttransfection of HEK 293T cells with the retroviral EGFR mutantexpression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs),pCMV-Gag-Pol vector and pCMV-VSV-G-Envelope vector. Briefly, HEK 293T/17cells were plated in 100 mm collagen coated plate (354450, Corning LifeSciences, Tewksbury, Mass.) (4×10⁵ per plate) and incubated overnight.The next day, retroviral plasmids (3 μg of EGFR mutant, 1.0 pg ofpCMV-Gag-Pol and 0.5 pg pCMV-VSV-G) were mixed in 500 μl of Optimem(31985, Life Technologies). The mixture was incubated at roomtemperature for 5 min and then added to Optimem containing transfectionreagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes.Mixture was then added dropwise to HEK 293T cells. The next day themedium was replaced with fresh culture medium and retrovirus washarvested @ 24 and 48 hrs.

Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells)were infected with 1 ml of viral supernatant supplemented with 8 pg/mlpolybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a37° C. incubator overnight. Cells were then spun for 5 minutes to pelletthe cells. Supernatant was removed and cells re-infected a fresh 1 ml ofviral supernatant supplemented with 8 pg/ml polybrene by centrifugingfor 30 min at 1000 rpm. Cells were placed in 37° C. incubator overnight.Cells were then maintained in RPMI containing 10% Heat Inactivated FBS,2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells wereselected for retroviral infection in 10 pg/mg Blasticidin for one week.Blasticidin resistant populations were washed twice in phosphatebuffered saline before plating in media lacking IL-3 to select for IL-3independent growth.

Assay for cell proliferation; BaF3 cell lines were resuspended at 1.3E5c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1%Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 wellplates. To determine the effect of drug on cell proliferation, cellsincubated for 3 days in the presence of vehicle control or test drug atvarying concentrations. Inhibition of cell growth was determined byluminescent quantification of intracellular ATP content usingCellTiterGlo (Promega), according to the protocol provided by themanufacturer. Comparison of cell number on day 0 versus 72 hours postdrug treatment was used to plot dose-response curves. The number ofviable cells was determined and normalized to vehicle-treated controls.Inhibition of proliferation, relative to vehicle-treated controls wasexpressed as a fraction of 1 and graphed using PRISM® software (GraphpadSoftware, San Diego, Calif.). EC₅₀ values were determined with the sameapplication.

Cellular protein analysis: Cell extracts were prepared by detergentlysis (RIPA, R0278, Sigma, St Louis, Mo.) containing 10 mM Iodoacetamide(786-228, G-Biosciences, St, Louis, Mo.), protease inhibitor (P8340,Sigma, St. Louis, Mo.) and phosphatase inhibitors (P5726, P0044, Sigma,St. Louis, Mo.) cocktails. The soluble protein concentration wasdetermined by micro-BSA assay (Pierce, Rockford Ill.). Proteinimmunodetection was performed by electrophoretic transfer of SDS-PAGEseparated proteins to nitrocellulose, incubation with antibody, andchemiluminescent second step detection. Nitrocellulose membranes wereblocked with 5% nonfat dry milk in TBS and incubated overnight withprimary antibody in 5% bovine serum albumin. The following primaryantibodies from Cell Signaling Technology were used at 1:1000 dilution:phospho-EGFR[Y1173] and total EGFR. β-Actin antibody, used as a controlfor protein loading, was purchased from Sigma Chemicals. Horseradishperoxidase-conjugated secondary antibodies were obtained from CellSignaling Technology and used at 1:5000 dilution. Horseradishperoxidase-conjugated secondary antibodies were incubated in nonfat drymilk for 1 hour. SuperSignal chemiluminescent reagent (PierceBiotechnology) was used according to the manufacturer's directions andblots were imaged using the Alpha Innotech image analyzer andAlphaEaseFC software (Alpha Innotech, San Leandro Calif.).

Uses of the Compounds and Compositions

In some aspects, the present disclosure is directed to a method ofinhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenicvariant of an EGFR), comprising administering the subject in needthereof a therapeutically effective amount of a compound describedherein.

In some aspects, the present disclosure is directed to a method ofinhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenicvariant of an EGFR), comprising administering the subject in needthereof a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in thesubject; and ii) administering the subject in need of the treatment atherapeutically effective amount of a compound described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in thesubject; and ii) administering the subject in need of the treatment acomposition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in abiological sample from the subject; and ii) administering the subject inneed of the treatment a therapeutically effective amount of a compounddescribed herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising: i) identifying a subjectcandidate as the subject in need of the treatment when that at least oneoncogenic variant of an ErbB receptor described herein is present in abiological sample from the subject; and ii) administering the subject inneed of the treatment a composition described herein.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein when that at least one oncogenic variant of an ErbB receptordescribed herein is identified as being present in the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a compound described herein when that at least oneoncogenic variant of an ErbB receptor described herein is identified asbeing present in the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a therapeutically effective amount of a compound describedherein when that at least one oncogenic variant of an ErbB receptordescribed herein is identified as being present in a biological samplefrom the subject.

In some aspects, the present disclosure is directed to a method ofpreventing or treating cancer, comprising administering the subject inneed thereof a composition described herein when that at least oneoncogenic variant of an ErbB receptor described herein is identified asbeing present in a biological sample from the subject.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the inhibition of an oncogenic variant of anErbB receptor (e.g., an oncogenic variant of an EGFR).

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the inhibition of an oncogenic variant of anErbB receptor (e.g., an oncogenic variant of an EGFR).

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in the subject.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in the subject.

In some aspects, the present disclosure is directed to a compounddescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in a biological sample from the subject.

In some aspects, the present disclosure is directed to a compositiondescribed herein for use in the prevention or treatment of cancer in asubject, wherein at least one oncogenic variant of an ErbB receptordescribed herein is present in a biological sample from the subject.

In some aspects, the present disclosure is directed to use of a compounddescribed herein in the manufacture of a medicament for inhibiting anoncogenic variant of an ErbB receptor (e.g., an oncogenic variant of anEGFR).

In some aspects, the present disclosure is directed to use of a compounddescribed herein in the manufacture of a medicament for preventing ortreating cancer.

In some embodiments, the compound is selected from the compoundsdescribed in Table 1, pharmaceutically acceptable salts thereof, andstereoisomers thereof.

In some embodiments, the compound is selected from the compoundsdescribed in Table 1 and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from the compoundsdescribed in Table 1.

In some embodiments, cancer is a solid tumor.

In some embodiments, the cancer is a bladder cancer, a breast cancer, acervical cancer, a colorectal cancer, an endometrial cancer, a gastriccancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, anon-small cell lung cancer (NSCLC), or any subtype thereof.

In some embodiments, the cancer is glioblastoma (GBM) or any subtypethereof.

In some embodiments, the cancer is glioblastoma.

The disclosure provides a composition comprising a compound of thedisclosure or pharmaceutically acceptable salts or stereoisomersthereof. In some embodiments, the composition comprises apharmaceutically acceptable carrier. In some embodiments, thecomposition composition comprises a second therapeutically active agent.In some embodiments, the second therapeutically active agent comprises asecond compound of the disclosure. In some embodiments, the secondtherapeutically active agent comprises a non-Type I inhibitor. In someembodiments, the non-Type I inhibitor comprises a Type II inhibitor. Insome embodiments, the Type II inhibitor comprises a small moleculeinhibitor.

The disclosure provides a composition of the disclosure for use in thetreatment of cancer, wherein the cancer or a tumor or a cell thereofexpresses an oncogenic variant of an epidermal growth factor receptor(EGFR).

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of an epidermal growthfactor receptor (EGFR), the oncogenic variant of an EGFR is anallosteric variant of EGFR.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesan oncogenic variant of an epidermal growth factor receptor (EGFR) andwherein the oncogenic variant of an EGFR is an allosteric variant ofEGFR, the oncogenic variant of an EGFR comprises an EGFR variant III(EGFR-Viii) mutation.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesan oncogenic variant of an epidermal growth factor receptor (EGFR) andwherein the oncogenic variant of an EGFR is an allosteric variant ofEGFR, the oncogenic variant of an EGFR comprises a substitution of avaline (V) for an alanine (A) at position 289 of SEQ ID NO: 1.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesan oncogenic variant of an epidermal growth factor receptor (EGFR) andwherein the oncogenic variant of an EGFR is an allosteric variant ofEGFR, the oncogenic variant of an EGFR comprises a modification of astructure of the EGFR, wherein the oncogenic variant of an EGFR is acapable of forming a covalently linked dimer, wherein the covalentlylinked dimer is constitutively active and wherein the covalently linkeddimer enhances an activity of EGFR when contacted to a Type I ErbBinhibitor. In some embodiments, the modification of the structure of theEGFR comprises a modification of one or more of a nucleic acid sequence,an amino acid sequence, a secondary structure, a tertiary structure, anda quaternary structure. In some embodiments, the oncogenic variantcomprises a mutation, a splicing event, a post-translational process, aconformational change or any combination thereof. In some embodiments,the modification of the structure of the EGFR occurs within a firstcysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. Insome embodiments, the first cysteine rich (CR1) and/or second cysteinerich (CR2) region of EGFR comprises amino acid residues T211-R334 and/orC526-S645 of SEQ ID NO: 1, respectively. In some embodiments, theoncogenic variant of an EGFR generates a physical barrier to formationof a disulfide bond within the CR1 and/or the CR2 region. In someembodiments, the oncogenic variant of an EGFR removes a physical barrierto formation of a disulfide bond within the CR1 and/or the CR2 region.In some embodiments, the oncogenic variant of an EGFR comprises one ormore free or unpaired Cysteine (C) residues located at a dimer interfaceof the EGFR. In some embodiments, the oncogenic variant of an EGFRcomprises one or more free or unpaired Cysteine (C) residues at a siteselected from the group consisting of C190-C199, C194-C207, C215-C223,C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307,C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555,C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636according to SEQ ID NO: 1. In some embodiments, the modification occurswithin 10 angstroms or less of an intramolecular disulfide bond at asite selected from the group consisting of C190-C199, C194-C207,C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291,C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535,C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 andC624-C636 according to SEQ ID NO: 1.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesoncogenic variant of EGFR and the oncogenic variant of EGFR is amutation of EGFR, a nucleotide sequence encoding the oncogenic variantof an EGFR comprises a deletion or a substitution of a sequence encodingexon 19 or a portion thereof. In some embodiments, the deletion or thesubstitution comprises one or more amino acids that encode an adenosinetriphosphate (ATP) binding site. In some embodiments, the ATP bindingsite comprises amino acids E746 to A750 of SEQ ID NO: 1. In someembodiments, the ATP binding site or the deletion or substitutionthereof comprises K858 of SEQ ID NO: 1. In some embodiments, thedeletion comprises K858 of SEQ ID NO: 1. In some embodiments, anarginine (R) is substituted for the lysine (K) at position 858 (K858R)of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted forthe leucine (L) at position 858 (L858R) of SEQ ID NO: 1.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesan oncogenic variant of an epidermal growth factor receptor (EGFR) andwherein the oncogenic variant of an EGFR is an allosteric variant ofEGFR, a nucleotide sequence encoding the oncogenic variant of an EGFRcomprises an insertion within a sequence encoding exon 20 or a portionthereof. In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO:7). In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding a C-helix, a terminal end of theC-helix or a loop following the C-helix. In some embodiments, theinsertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA.In some embodiments, the sequence encoding exon 20 or a portion thereofcomprises one or more of: (a) an insertion of the amino acid sequenceASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion ofthe amino acid sequence SVD between positions D770 and N771 of SEQ IDNO: 1; (c) an insertion of the amino acid sequence NPH between positionsH773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acidsequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) aninsertion of the amino acid sequence PH between positions H773 and V774of SEQ ID NO: 1; (f) an insertion of the amino acid G between positionsD770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid Hbetween positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of theamino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1;(i) an insertion of the amino acid sequence AH between positions H773and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequenceSVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitutionof the amino acid sequence GYN for the DN between positions 770 and 771of SEQ ID NO: 1; (l) an insertion of the amino acid H between positionsN771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Ybetween positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of theamino acid sequence PHVC between positions C775 and R776 of SEQ ID NO:1; (o) a substitution of the amino acid sequence YNPY for the H atposition 773 of SEQ ID NO: 1; (p) an insertion of the amino acidsequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) aninsertion of the amino acid sequence VDS between positions S768 and V769of SEQ ID NO: 1; (r) an insertion of the amino acid H between positionsD770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid Nbetween positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of theamino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1;(u) a substitution of the amino acid sequence GSVDN for the DN betweenpositions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the aminoacid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO:1; (w) an insertion of the amino acid G between positions N771 and P772of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP betweenpositions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the aminoacid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) asubstitution of the amino acid sequence GNPHVC for the VC betweenpositions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the aminoacid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb)an insertion of the amino acid sequence GL between positions D770 andN771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y betweenpositions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the aminoacid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee)an insertion of the amino acid sequence TH between positions H773 andV774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGPfor the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) asubstitution of the amino acid sequence SVDNP for the NP betweenpositions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the aminoacid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii)an insertion of the amino acid T between positions N771 and P772 of SEQID NO: 1; and (jj) a substitution of the amino acid sequence STLASV forthe SV between positions 768 and 769 of SEQ ID NO: 1.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, cancer or a tumor or a cell thereof expressesan oncogenic variant of an epidermal growth factor receptor (EGFR) andwherein the oncogenic variant of an EGFR is an allosteric variant ofEGFR, the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi,EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C,EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S,EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y,EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-A660,EGFR-A768 or any combination thereof.

The disclosure provides a composition of the disclosure for use in thetreatment of cancer, wherein the cancer, a tumor or a cell thereofexpresses one or more of: (a) a wild type human epidermal growth factorreceptor 2 (HER2) receptor or (b) an oncogenic variant of a HER-2receptor.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses a wild type HER-2 receptor, the wild typeHER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4,5, or 6.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor,the oncogenic variant of a HER2 receptor is an allosteric variant of theHER2 receptor.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a phenylalanine (F) for a serine (S) atposition 310 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a tyrosine (Y) for a serine (S) at position310 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a glutamine (Q) for an arginine (R) atposition 678 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a leucine (L) for a valine (V) at position777 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a methionine (M) for a valine (V) atposition 777 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of an isoleucine (I) for a valine (V) atposition 842 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of an alanine (A) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a proline (P) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a serine (S) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, a nucleotide sequence encoding theoncogenic variant of a HER2 receptor comprises an insertion within asequence encoding exon 20 or a portion thereof. In some embodiments, thesequence encoding exon 20 or a portion thereof comprises a sequenceencoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, thesequence encoding exon 20 or a portion thereof comprises a sequenceencoding a C-helix, a terminal end of the C-helix or a loop followingthe C-helix. In some embodiments, the insertion comprises the amino acidsequence of GSP or YVMA. In some embodiments, the sequence encoding exon20 or a portion thereof comprises one or more of: (a) an insertion ofthe amino acid sequence YVMA between positions A775 and G776 of SEQ IDNO: 2; (b) an insertion of the amino acid sequence GSP between positionsP780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acidsequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) aninsertion of the amino acid sequence YVMA between positions A775 andG776 of SEQ ID NO: 2; (e) an insertion of the amino acid V betweenpositions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the aminoacid V between positions V777 and G778 of SEQ ID NO: 2; (g) asubstitution of the amino acid sequence AVGCV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the aminoacid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) asubstitution of the amino acid sequence LCV for the G between position776 of SEQ ID NO: 2; ( ) an insertion of the amino acid sequence GSPbetween positions V777 and G778 of SEQ ID NO: 2; (k) a substitution ofthe amino acid sequence PS for the LRE between positions 755 and 757 ofSEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP forthe SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertionof the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n)a substitution of the amino acid sequence VVMA for the AG betweenpositions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the aminoacid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) asubstitution of the amino acid sequence AVCV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the aminoacid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO:2; (r) an insertion of the amino acid G between positions G778 and S779of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK forthe LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertionof the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u)an insertion of the amino acid sequence YAMA between positions A775 andG776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CVfor the G at position 776 of SEQ ID NO: 2; (w) a substitution of theamino acid sequence AVCGG for the GVG between positions 776 and 778 ofSEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for theGVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution ofthe amino acid sequence VVVG for the GVG between positions 776 and 778of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG forthe GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) asubstitution of the amino acid sequence VVGES for the GVGS betweenpositions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the aminoacid sequence AVGSGV for the GV between positions 776 and 777 of SEQ IDNO: 2; (cc) a substitution of the amino acid sequence CVC for the GVbetween positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution ofthe amino acid sequence HVC for the GV between positions 776 and 777 ofSEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV forthe GV between positions 776 and 777 of SEQ ID NO: 2; (ff) asubstitution of the amino acid sequence VAGV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the aminoacid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO:2; (hh) an insertion of the amino acid sequence FPG between positionsG778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acidsequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) asubstitution of the amino acid sequence VPS for the VLRE betweenpositions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the aminoacid E between positions V777 and G778 of SEQ ID NO: 2; (ll) aninsertion of the amino acid sequence MAGV between positions V777 andG778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S betweenpositions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the aminoacid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and(oo) an insertion of the amino acid sequence LMAY between positions Y772and V773 of SEQ ID NO: 2.

In some embodiments of the compositions for use in the treatment ofcancer of the disclosure, including those wherein the cancer or a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of the HER-2 receptor is an allostericvariant of the HER-2 receptor, the oncogenic variant of a HER2 receptorcomprises HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or anycombination thereof.

The disclosure provides a use of the composition of the disclosure fortreating cancer, comprising administering to a subject atherapeutically-effective amount of the composition, wherein the cancer,a tumor or a cell thereof expresses an oncogenic variant of an epidermalgrowth factor receptor (EGFR).

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR, theoncogenic variant of EGFR is an allosteric variant of EGFR.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR andwherein the oncogenic variant of EGFR is an allosteric variant of EGFR,the oncogenic variant of an EGFR comprises an EGFR variant III(EGFR-Viii) mutation.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR andwherein the oncogenic variant of EGFR is an allosteric variant of EGFR,the oncogenic variant of an EGFR comprises a substitution of a valine(V) for an alanine (A) at position 289 of SEQ ID NO: 1.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR andwherein the oncogenic variant of EGFR is an allosteric variant of EGFR,the oncogenic variant of an EGFR comprises a modification of a structureof the EGFR, wherein the oncogenic variant of an EGFR is a capable offorming a covalently linked dimer, wherein the covalently linked dimeris constitutively active and wherein the covalently linked dimerenhances an activity of EGFR when contacted to a Type I ErbB inhibitor.In some embodiments, the modification of the structure of the EGFRcomprises a modification of one or more of a nucleic acid sequence, anamino acid sequence, a secondary structure, a tertiary structure, and aquaternary structure. In some embodiments, the oncogenic variantcomprises a mutation, a splicing event, a post-translational process, aconformational change or any combination thereof. In some embodiments,the modification of the structure of the EGFR occurs within a firstcysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. Insome embodiments, the first cysteine rich (CR1) and/or second cysteinerich (CR2) region of EGFR comprises amino acid residues T211-R334 and/orC526-S645 of SEQ ID NO: 1, respectively. In some embodiments, theoncogenic variant of an EGFR generates a physical barrier to formationof a disulfide bond within the CR1 and/or the CR2 region. In someembodiments, the oncogenic variant of an EGFR removes a physical barrierto formation of a disulfide bond within the CR1 and/or the CR2 region.In some embodiments, the oncogenic variant of an EGFR comprises one ormore free or unpaired Cysteine (C) residues located at a dimer interfaceof the EGFR. In some embodiments, the oncogenic variant of an EGFRcomprises one or more free or unpaired Cysteine (C) residues at a siteselected from the group consisting of C190-C199, C194-C207, C215-C223,C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307,C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555,C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636according to SEQ ID NO: 1. In some embodiments, the modification occurswithin 10 angstroms or less of an intramolecular disulfide bond at asite selected from the group consisting of C190-C199, C194-C207,C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291,C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535,C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 andC624-C636 according to SEQ ID NO: 1.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of EGFR and theoncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequenceencoding the oncogenic variant of an EGFR comprises a deletion or thesubstitution comprises one or more amino acids that encode an adenosinetriphosphate (ATP) binding site. In some embodiments, the ATP bindingsite comprises amino acids E746 to A750 of SEQ ID NO: 1. In someembodiments, the ATP binding site or the deletion or substitutionthereof comprises K858 of SEQ ID NO: 1. In some embodiments, thedeletion comprises K858 of SEQ ID NO: 1. In some embodiments, anarginine (R) is substituted for the lysine (K) at position 858 (K858R)of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted forthe leucine (L) at position 858 (L858R) of SEQ ID NO: 1.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR andwherein the oncogenic variant of EGFR is an allosteric variant of EGFR,a nucleotide sequence encoding the oncogenic variant of an EGFRcomprises an insertion within a sequence encoding exon 20 or a portionthereof. In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO:7). In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding a C-helix, a terminal end of theC-helix or a loop following the C-helix. In some embodiments, theinsertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA.In some embodiments, the sequence encoding exon 20 or a portion thereofcomprises one or more of: (a) an insertion of the amino acid sequenceASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion ofthe amino acid sequence SVD between positions D770 and N771 of SEQ IDNO: 1; (c) an insertion of the amino acid sequence NPH between positionsH773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acidsequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) aninsertion of the amino acid sequence PH between positions H773 and V774of SEQ ID NO: 1; (f) an insertion of the amino acid G between positionsD770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid Hbetween positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of theamino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1;(i) an insertion of the amino acid sequence AH between positions H773and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequenceSVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitutionof the amino acid sequence GYN for the DN between positions 770 and 771of SEQ ID NO: 1; (l) an insertion of the amino acid H between positionsN771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Ybetween positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of theamino acid sequence PHVC between positions C775 and R776 of SEQ ID NO:1; (o) a substitution of the amino acid sequence YNPY for the H atposition 773 of SEQ ID NO: 1; (p) an insertion of the amino acidsequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) aninsertion of the amino acid sequence VDS between positions S768 and V769of SEQ ID NO: 1; (r) an insertion of the amino acid H between positionsD770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid Nbetween positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of theamino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1;(u) a substitution of the amino acid sequence GSVDN for the DN betweenpositions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the aminoacid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO:1; (w) an insertion of the amino acid G between positions N771 and P772of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP betweenpositions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the aminoacid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) asubstitution of the amino acid sequence GNPHVC for the VC betweenpositions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the aminoacid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb)an insertion of the amino acid sequence GL between positions D770 andN771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y betweenpositions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the aminoacid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee)an insertion of the amino acid sequence TH between positions H773 andV774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGPfor the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) asubstitution of the amino acid sequence SVDNP for the NP betweenpositions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the aminoacid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii)an insertion of the amino acid T between positions N771 and P772 of SEQID NO: 1; and (j) a substitution of the amino acid sequence STLASV forthe SV between positions 768 and 769 of SEQ ID NO. 1.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer or atumor or a cell thereof expresses an oncogenic variant of an EGFR andwherein the oncogenic variant of EGFR is an allosteric variant of EGFR,the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi,EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C,EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S,EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y,EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-A660,EGFR-A768 or any combination thereof.

The disclosure provides a use of a composition of the disclosure fortreating cancer, comprising administering to a subject atherapeutically-effective amount of the composition, wherein the cancer,a tumor or a cell thereof expresses one or more of: (a) a wild typehuman epidermal growth factor receptor 2 (HER2) receptor or an oncogenicvariant of a HER-2 receptor.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses a wild type HER-2 receptor, the wild typeHER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4,5, or 6.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor,the oncogenic variant of a HER2 receptor is an allosteric variant of theHER2 receptor.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a phenylalanine (F) for a serine (S) atposition 310 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a tyrosine (Y) for a serine (S) at position310 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a glutamine (Q) for an arginine (R) atposition 678 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a leucine (L) for a valine (V) at position777 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a methionine (M) for a valine (V) atposition 777 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of an isoleucine (I) for a valine (V) atposition 842 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of an alanine (A) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a proline (P) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises a substitution of a serine (S) for a leucine (L) at position755 of SEQ ID NO: 2 or 5.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, a nucleotide sequence encoding theoncogenic variant of a HER2 receptor comprises an insertion within asequence encoding exon 20 or a portion thereof.

In some embodiments, the sequence encoding exon 20 or a portion thereofcomprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). Insome embodiments, the sequence encoding exon 20 or a portion thereofcomprises a sequence encoding a C-helix, a terminal end of the C-helixor a loop following the C-helix. In some embodiments, the insertioncomprises the amino acid sequence of GSP or YVMA. In some embodiments,the sequence encoding exon 20 or a portion thereof comprises one or moreof: (a) an insertion of the amino acid sequence YVMA between positionsA775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acidsequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) aninsertion of the amino acid sequence YVMA between positions A771 andY772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMAbetween positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of theamino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) aninsertion of the amino acid V between positions V777 and G778 of SEQ IDNO: 2; (g) a substitution of the amino acid sequence AVGCV for the GVbetween positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of theamino acid sequence LC for the G between position 776 of SEQ ID NO: 2;(i) a substitution of the amino acid sequence LCV for the G betweenposition 776 of SEQ ID NO: 2; (j) an insertion of the amino acidsequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) asubstitution of the amino acid sequence PS for the LRE between positions755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acidsequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2;(m) an insertion of the amino acid C between positions V777 and G778 ofSEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for theAG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution ofthe amino acid sequence VV for the G at position 776 of SEQ ID NO: 2;(p) a substitution of the amino acid sequence AVCV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the aminoacid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO:2; (r) an insertion of the amino acid G between positions G778 and S779of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK forthe LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertionof the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u)an insertion of the amino acid sequence YAMA between positions A775 andG776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CVfor the G at position 776 of SEQ ID NO: 2; (w) a substitution of theamino acid sequence AVCGG for the GVG between positions 776 and 778 ofSEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for theGVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution ofthe amino acid sequence VVVG for the GVG between positions 776 and 778of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG forthe GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) asubstitution of the amino acid sequence VVGES for the GVGS betweenpositions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the aminoacid sequence AVGSGV for the GV between positions 776 and 777 of SEQ IDNO: 2; (cc) a substitution of the amino acid sequence CVC for the GVbetween positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution ofthe amino acid sequence HVC for the GV between positions 776 and 777 ofSEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV forthe GV between positions 776 and 777 of SEQ ID NO: 2; (ff) asubstitution of the amino acid sequence VAGV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the aminoacid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO:2; (hh) an insertion of the amino acid sequence FPG between positionsG778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acidsequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) asubstitution of the amino acid sequence VPS for the VLRE betweenpositions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the aminoacid E between positions V777 and G778 of SEQ ID NO: 2; (ll) aninsertion of the amino acid sequence MAGV between positions V777 andG778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S betweenpositions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the aminoacid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and(oo) an insertion of the amino acid sequence LMAY between positions Y772and V773 of SEQ ID NO: 2.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, including those wherein the cancer, a tumoror a cell thereof expresses an oncogenic variant of a HER-2 receptor andwherein the oncogenic variant of a HER2 receptor is an allostericvariant of the HER2 receptor, the oncogenic variant of a HER2 receptorcomprises HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or anycombination thereof.

The disclosure provides a use of a composition of the disclosure thetreatment of cancer, including those wherein the cancer, a tumor or acell thereof expresses an oncogenic variant of a HER-4 receptor. In someembodiments, the oncogenic variant of the HER-4 receptor is anallosteric variant of the HER4 receptor. In some embodiments, theoncogenic variant of a HER4 receptor comprises deletion of exon 16(HER4-A16).

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the composition is suitable for systemicadministration. In some embodiments, the composition is suitable fororal administration. In some embodiments, the composition is suitablefor intravenous administration

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the composition is suitable for localadministration. In some embodiments, the composition is suitable forintratumoral, intraocular, intraosseus, intraspinal orintracerebroventricular administration.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the subject or the cancer is insensitive orresistant to treatment with one or more of gefinitinib, erlotinib,afatinib, osimertinib, and necitunumab. In some embodiments, the subjector the cancer is insensitive or resistant to treatment with one or moreof crixotinib, alectinib, and ceritinib. In some embodiments, thesubject or the cancer is insensitive or resistant to treatment with oneor more of dabrafenib and trametinib. In some embodiments, the subjector the cancer is insensitive or resistant to treatment with crizotinib.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the cancer, tumor or cell thereof expressesan oncogenic variant of an EGFR, wherein the sequence encoding theoncogenic variant of the EGFR comprises a deletion of exon 20 or aportion thereof and wherein the cancer, tumor or cell thereof does notcomprise an oncogenic variation in a sequence encoding one or more of anEGFR kinase domain (KD), BRAF, NTRK, and KRAS or wherein.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the cancer, tumor or cell thereof comprisesan oncogenic variant of an EGFR, wherein the sequence encoding theoncogenic variant of the EGFR comprises a deletion of exon 20 or aportion thereof and wherein the cancer, tumor or cell thereof does notcomprise a marker indicating responsiveness to immunotherapy.

In some embodiments, the oncogenic variant (e.g., allosteric variant) orthe oncogenic mutation (e.g., allosteric mutation) is detected by a Foodand Drug Administration (FDA)-approved diagnosis.

In some embodiments, the subject has an adverse reaction to treatmentwith a therapeutic agent different from the compound of the presentdisclosure. In some embodiments, the subject has an adverse reaction totreatment with a Type I inhibitor. In some embodiments, the subject hasan adverse reaction to treatment with one or more of gefinitinib,erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib,ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib,canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. Insome embodiments, the adverse reaction is an activation of the oncogenicvariant of an EGFR and wherein the oncogenic variant comprises amutation in an extracellular domain of the receptor. In someembodiments, the adverse reaction is an activation of the oncogenicvariant of a HER-2 Receptor and wherein the oncogenic variant comprisesa mutation in an extracellular domain of the receptor.

In some embodiments, the method comprises administering to the subjectin need thereof a therapeutically effective amount of a non-Type Iinhibitor. In some embodiments, the non-Type I inhibitor comprises asmall molecule Type II inhibitor.

In some embodiments, the method comprises administering to the subjectin need thereof a therapeutically effective amount of a non-Type Iinhibitor. In some embodiments, the non-Type I inhibitor comprises asmall molecule Type H inhibitor.

In some embodiments, the compound is used in combination with atherapeutically effective amount of a non-Type I inhibitor. In someembodiments, the non-Type I inhibitor comprises a small molecule Type IIinhibitor.

In some embodiments, the composition comprises a non-Type I inhibitor.In some embodiments, the non-Type I inhibitor comprises a small moleculeType II inhibitor.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the cancer comprises a solid tumor. In someembodiments, the cancer comprises a bladder cancer, a breast cancer, acervical cancer, a colorectal cancer, an endometrial cancer, a gastriccancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, anon-small cell lung cancer (NSCLC) or any subtype thereof. In someembodiments, the cancer comprises a glioblastoma (GBM). In someembodiments, the cancer comprises a breast cancer. In some embodiments,the cancer comprises a lung cancer.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the therapeutically effective amountreduces a severity of a sign or symptom of the cancer. In someembodiments, the sign of the cancer comprises a tumor grade and whereina reduction of the severity of the sign comprises a decrease of thetumor grade. In some embodiments, the sign of the cancer comprises atumor metastasis and wherein a reduction of the severity of the signcomprises an elimination of the metastasis or a reduction in the rate orextent the metastasis. In some embodiments, the sign of the cancercomprises a tumor volume and wherein a reduction of the severity of thesign comprises an elimination of the tumor or a reduction in the volume.In some embodiments, the symptom of the cancer comprises pain andwherein a reduction of the severity of the sign comprises an eliminationor a reduction in the pain.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the therapeutically effective amountinduces a period of remission.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the therapeutically effective amountimproves a prognosis of the subject.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the subject is a participant or a candidatefor participation in in a clinical trial or protocol thereof. In someembodiments, the subject is excluded from treatment with a Type Iinhibitor. In some embodiments, the Type I inhibitor comprisesgefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib,alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib,dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 orAZD9291.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the use comprises treating the subject witha Non-Type I inhibitor.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the composition comprises a Non-Type Iinhibitor.

In some embodiments of the uses of the compositions of the disclosurefor the treatment of cancer, the Non-Type I inhibitor comprises a TypeII small molecule inhibitor. In some embodiments, the Type II smallmolecule inhibitor comprises neratinib, AST-1306, HKI-357, or lapatinib.

In some embodiments, the oncogenic variant is an oncogenic variant in anErbB receptor.

In some embodiments, the oncogenic variant in the ErbB receptor is anallosteric variant.

In some embodiments, the ErbB receptor is an epidermal growth factorreceptor (EGFR) or a human epidermal growth factor receptor 2 (HER2)receptor.

In some embodiments, the ErbB receptor is an epidermal growth factorreceptor (EGFR).

In some embodiments, the ErbB receptor is a HER2 receptor.

In some embodiments, the oncogenic variant is an oncogenic variant in anepidermal growth factor receptor (EGFR).

In some embodiments, the oncogenic variant in the EGFR is an allostericvariant.

In some embodiments, the oncogenic variant is an oncogenic variant of aHER2 receptor.

In some embodiments, the oncogenic variant in the HER2 receptor is anallosteric variant.

In some embodiments, the oncogenic variant in the EGFR is an EGFRvariant III (EGFR-Viii) variant.

In some embodiments, the oncogenic variant in the EGFR is a substitutionof a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR and wherein the oncogenic variant in the EGFR is an allostericvariant in the EGFR, the oncogenic variant in the EGFR is a modificationof a structure of the EGFR, wherein the oncogenic variant in the EGFR iscapable of forming a covalently linked dimer, wherein the covalentlylinked dimer is constitutively active and wherein the covalently linkeddimer enhances an activity of EGFR when contacted to a Type I ErbBinhibitor. In some embodiments, the modification of the structure of theEGFR comprises a modification of one or more of a nucleic acid sequence,an amino acid sequence, a secondary structure, a tertiary structure, anda quaternary structure. In some embodiments, the modification of thestructure of the EGFR occurs within a first cysteine rich (CR1) and/orsecond cysteine rich (CR2) region of EGFR. In some embodiments, thefirst cysteine rich (CR1) and/or second cysteine rich (CR2) region ofEGFR comprises amino acid residues T211-R³³⁴ and/or C526-S645 of SEQ IDNO: 1, respectively. In some embodiments, the oncogenic variant in theEGFR generates a physical barrier to formation of a disulfide bondwithin the CR1 and/or the CR2 region. In some embodiments, the oncogenicvariant in the EGFR removes a physical barrier to formation of adisulfide bond within the CR1 and/or the CR2 region. In someembodiments, the oncogenic variant in the EGFR results into one or morefree or unpaired Cysteine (C) residues located at a dimer interface ofthe EGFR. In some embodiments, the oncogenic variant in the EGFR resultsinto one or more free or unpaired Cysteine (C) residues at a siteselected from the group consisting of C190-C199, C194-C207, C215-C223,C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307,C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555,C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636according to SEQ ID NO: 1. In some embodiments, the modification occurswithin 10 angstroms or less of an intramolecular disulfide bond at asite selected from the group consisting of C190-C199, C194-C207,C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291,C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535,C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 andC624-C636 according to SEQ ID NO: 1.

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR and wherein the oncogenic variant in the EGFR is an allostericvariant in the EGFR, wherein a nucleotide sequence encoding the EGFRhaving the oncogenic variant comprises a deletion or the substitutioncomprises one or more amino acids that encode an adenosine triphosphate(ATP) binding site. In some embodiments, the ATP binding site comprisesamino acids E746 to A750 of SEQ ID NO: 1.

In some embodiments, the ATP binding site or the deletion orsubstitution thereof comprises K858 of SEQ ID NO: 1. In someembodiments, the deletion comprises K858 of SEQ ID NO: 1. In someembodiments, an arginine (R) is substituted for the lysine (K) atposition 858 (K858R) of SEQ ID NO: 1. In some embodiments, an arginine(R) is substituted for the leucine (L) at position 858 (L858R) of SEQ IDNO: 1.

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR and wherein the oncogenic variant in the EGFR is an allostericvariant in the EGFR, wherein a nucleotide sequence encoding the EGFRhaving the oncogenic variant comprises an insertion within a sequenceencoding exon 20 or a portion thereof. In some embodiments, the sequenceencoding exon 20 or a portion thereof comprises a sequence encodingKEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequenceencoding exon 20 or a portion thereof comprises a sequence encoding aC-helix, a terminal end of the C-helix or a loop following the C-helix.In some embodiments, the insertion comprises the amino acid sequence ofASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon20 or a portion thereof comprises one or more of: (a) an insertion ofthe amino acid sequence ASV between positions V769 and D770 of SEQ IDNO: 1; (b) an insertion of the amino acid sequence SVD between positionsD770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acidsequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) aninsertion of the amino acid sequence FQEA between positions A763 andY764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PHbetween positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of theamino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) aninsertion of the amino acid H between positions H773 and V774 of SEQ IDNO: 1; (h) an insertion of the amino acid sequence HV between positionsV774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acidsequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) aninsertion of the amino acid sequence SVA between positions A767 and S768of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN forthe DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertionof the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m)an insertion of the amino acid Y between positions H773 and V774 of SEQID NO: 1; (n) an insertion of the amino acid sequence PHVC betweenpositions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the aminoacid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) aninsertion of the amino acid sequence DNP between positions P772 and H773of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS betweenpositions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the aminoacid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertionof the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t)an insertion of the amino acid sequence PNP between positions P772 andH773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequenceGSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) asubstitution of the amino acid sequence GYP for the NP between positions771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid Gbetween positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of theamino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1;(y) an insertion of the amino acid sequence GSV between positions V769and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequenceGNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) aninsertion of the amino acid sequence LQEA between positions A763 andY764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GLbetween positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion ofthe amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd)an insertion of the amino acid sequence NPY between positions H773 andV774 of SEQ ID NO. 1; (ee) an insertion of the amino acid sequence THbetween positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution ofthe amino acid sequence KGP for the NP between positions 771 and 772 ofSEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP forthe NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertionof the amino acid sequence NN between positions N771 and P772 of SEQ IDNO: 1; (ii) an insertion of the amino acid T between positions N771 andP772 of SEQ ID NO: 1; and (j) a substitution of the amino acid sequenceSTLASV for the SV between positions 768 and 769 of SEQ ID NO: 1.

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR and wherein the oncogenic variant in the EGFR is an allostericvariant in the EGFR, the EGFR having the oncogenic variant comprisesEGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y,EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y,EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A,EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y,EGFR-G645C, EGFR-A660, EGFR-A768 or any combination thereof.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor, the oncogenic variant in the HER2 receptor is anallosteric variant in the HER2 receptor.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a phenylalanine (F) for aserine (S) at position 310 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a tyrosine (Y) for a serine(S) at position 310 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a glutamine (Q) for anarginine (R) at position 678 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a leucine (L) for a valine (V)at position 777 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a methionine (M) for a valine(V) at position 777 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of an isoleucine (I) for a valine(V) at position 842 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of an alanine (A) for a leucine(L) at position 755 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a proline (P) for a leucine(L) at position 755 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the oncogenic mutatin in theHER2 receptor comprises a substitution of a serine (S) for a leucine (L)at position 755 of SEQ ID NO: 2 or 5.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, wherein a nucleotidesequence encoding the HER2 receptor having the oncogenic variantcomprises an insertion within a sequence encoding exon 20 or a portionthereof. In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO:8). In some embodiments, the sequence encoding exon 20 or a portionthereof comprises a sequence encoding a C-helix, a terminal end of theC-helix or a loop following the C-helix. In some embodiments, theinsertion comprises the amino acid sequence of GSP or YVMA. In someembodiments, the sequence encoding exon 20 or a portion thereofcomprises one or more of: (a) an insertion of the amino acid sequenceYVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertionof the amino acid sequence GSP between positions P780 and Y781 of SEQ IDNO: 2; (c) an insertion of the amino acid sequence YVMA betweenpositions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the aminoacid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e)an insertion of the amino acid V between positions V777 and G778 of SEQID NO: 2; (f) an insertion of the amino acid V between positions V777and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequenceAVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) asubstitution of the amino acid sequence LC for the G between position776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCVfor the G between position 776 of SEQ ID NO: 2; (j) an insertion of theamino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2;(k) a substitution of the amino acid sequence PS for the LRE betweenpositions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the aminoacid sequence CPGSP for the SP between positions 779 and 780 of SEQ IDNO: 2; (m) an insertion of the amino acid C between positions V777 andG778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMAfor the AG between positions 775 and 776 of SEQ ID NO: 2; (o) asubstitution of the amino acid sequence VV for the G at position 776 ofSEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for theGV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution ofthe amino acid sequence VCV for the GV between positions 776 and 777 ofSEQ ID NO: 2; (r) an insertion of the amino acid G between positionsG778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acidsequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2;(t) an insertion of the amino acid V between positions A775 and G776 ofSEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA betweenpositions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the aminoacid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) asubstitution of the amino acid sequence AVCGG for the GVG betweenpositions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the aminoacid sequence CVCG for the GVG between positions 776 and 778 of SEQ IDNO: 2; (y) a substitution of the amino acid sequence VVVG for the GVGbetween positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of theamino acid sequence SVGG for the GVGS between positions 776 and 779 ofSEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES forthe GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) asubstitution of the amino acid sequence AVGSGV for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the aminoacid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO:2; (dd) a substitution of the amino acid sequence HVC for the GV betweenpositions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the aminoacid sequence VAAGV for the GV between positions 776 and 777 of SEQ IDNO: 2; (ff) a substitution of the amino acid sequence VAGV for the GVbetween positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution ofthe amino acid sequence VVV for the GV between positions 776 and 777 ofSEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG betweenpositions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the aminoacid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (j) asubstitution of the amino acid sequence VPS for the VLRE betweenpositions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the aminoacid E between positions V777 and G778 of SEQ ID NO: 2; (ll) aninsertion of the amino acid sequence MAGV between positions V777 andG778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S betweenpositions V777 and G778 of SEQ ID NO. 2; (nn) an insertion of the aminoacid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and(oo) an insertion of the amino acid sequence LMAY between positions Y772and V773 of SEQ ID NO: 2.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-2 receptor and wherein the oncogenic variant in the HER2 receptor isan allosteric variant in the HER2 receptor, the HER2 receptor having theoncogenic variant comprises HER2-Δ16, HER2-C311R, HER2-S310F,p95-HER2-M611 or any combination thereof.

In some embodiments, the oncogenic variant is an oncogenic variant in aHER-4 receptor. In some embodiments, the oncogenic variant in the HER-4receptor is an allosteric variant in the HER4 receptor. In someembodiments, the oncogenic variant in the HER4 receptor results into thedeletion of exon 16 (HER4-A16).

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR, wherein the sequence encoding the EGFR having the oncogenicvariant comprises a deletion of exon 20 or a portion thereof and whereinthe cancer, the tumor or the cell thereof does not comprise a secondoncogenic variant in a sequence other than exon 20 of EGFR. In someembodiments, the second oncogenic variation comprises a sequenceencoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, andKRAS.

In some embodiments, the oncogenic variant is an oncogenic variant in anEGFR, wherein the sequence encoding the EGFR having the oncogenicvariant comprises a deletion of exon 20 or a portion thereof and whereinthe cancer, the tumor or the cell thereof does not comprise a markerindicating responsiveness to immunotherapy.

EXAMPLES Example 1. Synthesis of Exemplary Compounds of the PresentDisclosure

Step A.1:

A solution of 7-fluoro-6-nitro-quinazolin-4-ol (5.00 g, 23.9 mmol, 1.00eq) in thionyl chloride (20.0 mL) was added dimethyl formamide (174 mg,2.39 mmol, 183 uL, 0.10 eq). The reaction was stirred at 80° C. for 10h. The reaction mixture was concentrated under reduced pressure to give4-chloro-7-fluoro-6-nitroquinazoline (6.00 g, crude) as an off-whitesolid. The product was taken to next step without purification.

Step A.2:

A mixture of 4-chloro-7-fluoro-6-nitroquinazoline (2.4 g, 10.55 mmol, 1eq) and the free amine H₂N—X (1 eq) in isopropyl alcohol was heated at80° C. for 1 h. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was triturated with ethylacetate to give amine III.

Step A.3:

To a solution of amine III (1 eq) and the NH or OH nucleophile Z-L-Y²—H(1.1 eq) in acetonitrile was added cesium carbonate (2eq) or DBU (2eq)and optionally potassium iodide (1 eq). Then the mixture was stirred at80-110° C. for 12 h. The reaction mixture was quenched by addition ofwater and then extracted with ethyl acetate. The combined organic layerswere washed with brine dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography to give IV.

Step A.4:

Variant i): A mixture of IV (1 eq) and nickel(ii) chloride hexahydrate(2 eq) in dichloromethane and methanol (1:1) was added sodiumborohydride (4 eq) at 0° C. and then the mixture was stirred at 0° C.for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine V.

Variant ii): A mixture of IV (1 eq), iron (3 eq) and ammonium chloride(5 eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine V.

Step A.5:

Variant i): To a solution of V (1 eq), 4-dimethylaminopyridine (1.5 eq)and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide VI.

Variant ii): To a solution of V (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide VI.

Variant iii): To a solution of V (1.0 eq) in dimethylformamide was addedtriethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h and subsequently filtered.The filtrate was purified by prep-HPLC to give acrylamide VI.

Step A.6:

To a solution of V (1.0 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 eq)and pyridine (5.00 eq) in N,N-dimethylformamide was added but-2-ynoicacid (10.0 eq). The mixture was stirred at 50° C. for 2 h andsubsequently concentrated in vacuum. The mixture was purified byprep-HPLC to give ynamide VII.

Step B.1:

To a solution of HI, obtained in step A.2 (1.00 eq) and potassiumtert-butoxide (4.00 eq) in dimethylsulfoxide (10.0 mL) was added thecorresponding diol of aminoalcohol (6.00 eq) dropwise at 20° C. Themixture was stirred at 20° C. for 12 h. The mixture was diluted withwater and extracted with ethyl acetate. The combined organic layer waswashed with brine and dried over sodium sulfate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel chromatography to give alcohol VIII.

Step B.2:

Variant i): To a solution of VIII (1 eq) and triethylamine (4.00 eq) indichloromethane and dimethylsulfoxide (6:1) was added MsCl (4.00 eq)dropwise at 0° C. The mixture was stirred at 20° C. for 2 h. The mixturewas diluted with water and extracted with dichloromethane. The combinedorganic layer was washed with brine and dried over sodium sulfate,filtered and concentrated to give Mesylate IX.

Variant ii): To a solution of VIII (1.0 eq) in thionyl chloride wasadded N,N-dimethylformamide (0.1 eq). The mixture was stirred at 90° C.for 3 h. The mixture was cooled to 25° C. and then concentrated invacuum. The mixture was partitioned between and ethyl acetate. Theorganic phase was washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to afford chloride IX.

Step B.3:

To a solution of IX (1.0 eq) and potassium carbonate (4.00 eq) indimethylsulfoxide was the corresponding N—H nucleophile (2.0 eq) in oneportion at 20° C. The mixture was stirred at 50° C. for 12 h. Themixture was diluted with water and extracted with ethyl acetate. Thecombined organic layer was washed with brine and dried over sodiumsulfate, filtered and concentrated to give crude product. The crudeproduct was purified by prep-HPLC to give X.

Step B.4:

Variant i): A mixture of X (1 eq) and nickel(ii) chloride hexahydrate (2eq) in dichloromethane and methanol (1:1) was added sodium borohydride(4 eq) at 0° C. and then the mixture was stirred at 0° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated to givea residue. The residue was purified by reversed phase columnchromatography to give amine XI.

Variant ii): A mixture of X (1 eq), iron (3 eq) and ammonium chloride (5eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XI.

Step B.5:

Variant i): To a solution of XI (1 eq), 4-dimethylaminopyridine (1.5 eq)and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Variant ii): To a solution of XI (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Variant iii): To a solution of XI (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamide XII.

Step C.1:

Sodium (3.0 eq) vas added to the corresponding diol (18.7 eq) at 25° C.The suspension was stirred at 25° C. for 0.5 h. Alcohol I (1.0 eq) wasadded to the above suspension. The mixture was heated to 70° C. andstirred at 70° C. for 1.5 h. The mixture was cooled to 25° C. and thenadjusted to pH=7 with hydrochloric acid (3 M). After filtration, thefilter cake was dried under reduced pressure to afford diol XIII.

Step C.2:

To a solution of diol XIII (1.00 eq) in thionyl chloride (10.0 mL) wasadded N,N-dimethylformamide (0.1 eq). The mixture was stirred at 90° C.for 3 h. The mixture was cooled to 25° C. and then concentrated invacuum. The mixture was partitioned between water and ethyl acetate. Theorganic phase was washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to afford dichloride XIV.

Step C.3:

A solution of dichloride XIV (1.0 eq) and H₂N—X (1.50 eq) in propan-2-olwas stirred at 90° C. for 12 h. The mixture was cooled to 25° C. andthen concentrated in vacuum. The residue was triturated with methanol,then filtered and dried under reduced pressure to afford XV.

Step C.4:

To a solution of XV (1.0 eq), potassium iodide (0.1 eq) andtetrabutylammonium iodide (0.1 eq) in toluene was added HNR′R″ (3.00eq). The mixture was stirred at 110° C. for 12 h. The mixture was cooledto 25° C. and then concentrated in vacuum. The residue was trituratedwith water and filtered, the filter cake was dried in vacuum to affordXVI.

Step C.5:

Variant i): A mixture of XVI (1 eq) and nickel(ii) chloride hexahydrate(2 eq) in dichloromethane and methanol (1:1) was added sodiumborohydride (4 eq) at 0° C. and then the mixture was stirred at 0° C.for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine XVII.

Variant ii): A mixture of XVI (1 eq), iron (3 eq) and ammonium chloride(5 eq) in methanol and water (4:1) was stirred at 70° C. for 12 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XVII.

Step C₁₋₆:

Variant i): To a solution of XVII (1 eq), 4-dimethylaminopyridine (1.5eq) and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Variant ii): To a solution of XVI (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Variant iii): To a solution of XVII (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamideXVIII.

Steps C.7.

To a solution of XVII (1.0 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 eq)and pyridine (5.00 eq) in N,N-dimethylformamide was added but-2-ynoicacid (10.0 eq). The mixture was stirred at 50° C. for 2 h andsubsequently concentrated in vacuum. The mixture was purified byprep-HPLC to give ynamide XIX.

Step D.1:

To a solution of bromide or triflate XX (1.00 eq) in dimethylsulfoxidewas added the corresponding alkyne (1.50 eq), triethylamine (3.00 eq),copper (I) iodide (0.5 eq), tetrakis(triphenylphosphine)palladium (0.05eq) at 20° C. The mixture was degassed with nitrogen and stirred at 20°C. for 12 h under nitrogen. The mixture was added methanol and filtered,the filter cake was concentrated to give alkyne XXI.

Step D.2:

To a suspension of alkyne XXI (1.00 eq) in thionyl chloride was addedN,N-dimethylformamide (2.0 eq) at 20° C. The mixture was stirred at 90°C. for 0.5 h until the suspension turned to homogenous solution. Thesolution was concentrated to give chloride XXII.

Step D.3:

A suspension of chloride XXII (1.0 eq) and H₂N—X in propan-2-ol wasstirred at 80° C. for 12 h. The mixture was concentrated to give aresidue. And the residue was purified by reverse phase chromatography togive XXIII.

Step D.4:

Variant i): A mixture of XXIII (1 eq) and nickel(ii) chloridehexahydrate (2 eq) in dichloromethane and methanol (1:1) was addedsodium borohydride (4 eq) at 0° C. and then the mixture was stirred at0° C. for 12 h. The reaction mixture was filtered and the filtrate wasconcentrated to give a residue. The residue was purified by reversedphase column chromatography to give amine XXIV.

Variant ii): A mixture of XXIII (1 eq), iron (3 eq) and ammoniumchloride (5 eq) in methanol and water (4:1) was stirred at 70° C. for 12h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give a residue. The residue was purified byReverse-MPLC to give amine XXIV.

Step D.5:

Variant i): To a solution of XXIV (1 eq), 4-dimethylaminopyridine (1.5eq) and acrylic acid (1.2 eq) in dimethyl formamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq) and then thesolution was stirred at 25° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Variant ii): To a solution of XXIV (1 eq) and triethylamine (4 eq) indimethyl formamide was added acrylic anhydride (1.2 eq) and then thesolution was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Variant iii): To a solution of XXIV (1.0 eq) in dimethylformamide wasadded triethylamine (3.00 eq) and acryloyl chloride (1.20 eq) at 0° C.The reaction mixture was stirred at 0° C. for 1 h and subsequentlyfiltered. The filtrate was purified by prep-HPLC to give acrylamide XXV.

Compound No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

1801: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-((3-fluorobenzyl)oxy)aniline (995 mg, 3.95 mmol);in step A.3 the NH nucleophile is N¹,N¹,N²-trimethylethane-1,2-diamine(254 mg, 2.48 mmol); variant i) was used in step A.4; and variant ii)was used in step A.5, and 8% overall yield from II. ¹H NMR (400 MHz,DMSO-d₆) δ=10.14 (br s, 1H), 9.69 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H),7.98 (s, 1H), 7.71 (br d, 0.1=8.8 Hz, 1H), 7.53-7.42 (m, 1H), 7.37 (s,1H), 7.36-7.30 (m, 2H), 7.25 (br d, J=9.0 Hz, 1H), 7.19 (br t, J=8.6 Hz,1H), 6.57 (br dd, J=10.0, 16.8 Hz, 1H), 6.34 (br d, J=16.8 Hz, 1H), 5.85(br d, J=10.6 Hz, 1H), 5.25 (s, 2H), 2.99 (br d, J=5.8 Hz, 2H), 2.86 (s,3H), 2.48-2.46 (m, 2H), 2.19 (s, 6H). MS (ESI) m/z 549.1 [M+H]⁺2: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-((3-fluorobenzyl)oxy)aniline (995 mg, 3.95 mmol);in step A.3 the NH nucleophile is N-methyl-2-morpholino-ethanamine(234.49 mg, 1.63 mmol); variant i) was used in step A.4; and variant i)was used in step A.5; and 16% overall yield from 1. ¹H NMR (400 MHz,CDCl₃) δ=8.53 (s, 1H), 8.38 (s, 1H), 7.71 (br d, J=2.0 Hz, 1H), 7.43 (brdd, J=2.0, 8.8 Hz, 1H), 7.31-7.24 (m, 1H), 7.21-7.19 (m, 1H), 7.18-7.10(m, 2H), 6.94 (br t, J=7.2 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.05 (s,2H), 3.59-3.44 (m, 4H), 3.26 (br t, J=6.6 Hz, 2H), 2.87 (s, 3H), 2.53(br t, J=6.6 Hz, 2H), 2.41-2.28 (m, 4H), 1.97 (s, 2H). MS (ESI) m/z567.1 [M+H]⁺3: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-((3-fluorobenzyl)oxy)aniline (995 mg, 3.95 mmol);in step A.3 the OH nucleophile is 3-morpholinopropan-1-ol (275 mg, 1.90mmol); variant ii) was used in step A.4; and variant i) was used in stepA.5; and 2% overall yield from II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s,1H), 9.61 (s, 1H), 8.84 (s, 1H), 8.49 (s, 1H), 7.99 (d, J=2.5 Hz, 1H),7.70 (dd, J=2.5, 8.9 Hz, 1H), 7.53-7.42 (m, 1H), 7.37-7.29 (m, 2H),7.28-7.22 (m, 2H), 7.22-7.14 (m, 1H), 6.71 (br dd, J=10.3, 17.2 Hz, 1H),6.32 (dd, J=1.8, 17.2 Hz, 1H), 5.94-5.74 (m, 1H), 5.25 (s, 2H), 4.26 (t,J=6.4 Hz, 2H), 3.58 (t, J=4.6 Hz, 4H), 2.49-2.45 (m, 2H), 2.38 (br s,4H), 1.99 (quin, J=6.6 Hz, 2H). MS (ESI) m/z 592.0 [M+H]⁺4: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-(pyridin-2-ylmethoxy)aniline (3.50 g, 14.9 mmol);in step A.3 the OH nucleophile is 3-morpholinopropan-1-ol (275 mg, 1.90mmol); variant ii) was used in step A.4, and variant i) was used in stepA.5; and 2% overall yield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.05 (s,1H), 8.89 (s, 1H), 8.63-8.58 (m, 2H), 7.92 (s, 1H), 7.88 (d, J=2.4 Hz,1H), 7.79-7.73 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (dd, J=8.8, 2.8 Hz,1H), 7.26-7.23 (m, 1H), 7.00 (d, J=5.2 Hz, 1H), 5.30 (s, 2H), 4.35 (t,J=5.6 Hz, 2H), 3.82-3.78 (m, 4H), 2.90 (t, J=5.6 Hz, 2H), 2.63-2.59 (m,4H), 2.08 (s, 3H). MS (ESI) m/z 573.4 [M+H]⁺5: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-(pyridin-2-ylmethoxy)aniline (3.50 g, 14.9 mmol);in step A.3 the NH nucleophile is N-methyl-2-morpholinoethanamine (508mg, 3.52 mmol); variant i) was used in step A.4; and variant ii) wasused in step A.5; and 4% overall yield from II. ¹H NMR (400 MHz, CDCl₃)δ=9.05 (s, 1H), 8.89 (s, 1H), 8.63-8.58 (m, 2H), 7.92 (s, 1H), 7.88 (d,J=2.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (dd,J=8.8, 2.8 Hz, 1H), 7.26-7.23 (m, 1H), 7.00 (d, J=5.2 Hz, 1H), 5.30 (s,2H), 4.35 (t, J=5.6 Hz, 2H), 3.82-3.78 (m, 4H), 2.90 (t, J=5.6 Hz, 2H),2.63-2.59 (m, 4H), 2.08 (s, 3H). MS (ESI) m/z 573.4 [M+H]⁺6: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline (700 mg,2.60 mmol); in step A.3 the OH nucleophile is 2-morpholinoethanol (569mg, 4.34 mmol, 532 uL); variant i) was used in step A.4; and variant ii)was used in step A.5; and 1% overall yield from III. ¹H NMR (400 MHz,DMSO-d₆) δ=9.67 (br d, J=9.0 Hz, 2H), 8.86 (s, 1H), 8.38 (s, 1H), 7.60(d, J=8.0 Hz, 1H) 7.54-7.46 (m, 1H) 7.40-7.29 (m, 4H) 7.26-7.15 (m, 1H)6.71 (dd, J=17.0, 10.2 Hz, 1H), 6.38-6.25 (m, 1H), 5.87-5.78 (m, 1H),5.30 (s, 2H), 4.35 (t, J=5.8 Hz, 2H) 3.63-3.53 (m, 4H) 2.84 (t, J=5.6Hz, 2H) 2.52-2.53 (m, 4H). MS (ESI) m/z 596.3 [M+H]⁺7: Synthesized according to general procedure A starting fromintermediate V (300 mg, 530 umol) obtained in 5, variant ii) was used instep A.5; and 16% overall yield from V. ¹H NMR (400 MHz, DMSO-d₆) δ=9.75(br s, 1H), 9.67 (br s, 1H), 8.69-8.55 (m, 2H), 8.47 (s, 1H), 8.00 (d,J=2.4 Hz, 1H), 7.89 (dt, J=7.6, 1.6 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.38 (dt, J=6.2, 1.0 Hz, 1H), 7.29 (s, 1H),7.25 (d, J=9.2 Hz, 1H), 6.68 (br dd, J=16.8, 10.0 Hz, 1H), 6.33 (dd,J=17.0, 2.0 Hz, 1H), 5.87-5.79 (m, 1H), 5.29 (s, 2H), 3.57-3.44 (m, 4H),3.14 (br t, J=7.0 Hz, 2H), 2.88 (s, 3H), 2.53 (br s, 2H), 2.31 (br s,4H). MS (ESI) m/z 574.1 [M+H]⁺8: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-(pyridin-2-ylmethoxy)aniline (3.50 g, 14.9 mmol);in step A.3 the OH nucleophile is 2-morpholinoethanol (179 mg, 1.37mmol); variant i) was used in step A.4; and variant i) was used in stepA.5; and 21% overall yield from II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s,1H), 9.62 (s, 1H), 8.83 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.49 (s, 1H),7.99 (d, J=2.4 Hz, 1H), 7.88 (dt, J=1.2, 7.6 Hz, 1H), 7.69 (dd, J=2.4,9.0 Hz, 1H), 7.59 (d, 0.1=8.0 Hz, 1H), 7.41-7.34 (m, 1H), 7.31 (s, 1H),7.25 (d, J=9.2 Hz, 1H), 6.68 (br dd, J=10.8, 17.2 Hz, 1H), 6.31 (dd,J=16.8, 1.2 Hz, 1H), 5.82 (br d, 0.1=11.6 Hz, 1H), 5.29 (s, 2H), 4.34(t, 1=5.6 Hz, 2H), 3.57 (t, J=4.4 Hz, 4H), 3.32 (br s, 4H), 2.82 (t,J=5.6 Hz, 2H). MS (ESI) m/z 561.4 [M+H]⁺9: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-(2-pyridylmethoxy)aniline (3.00 g, 14.9 mmol); in step A.3the OH nucleophile is 2-imidazol-1-ylethanol (137 mg, 1.23 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 1% overall yield from II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.63 (s, 1H),9.55 (s, 1H), 8.84 (s, 1H), 8.59 (d, J=3.6 Hz, 1H), 8.41 (s, 1H), 7.85(dt, J=1.6, 7.6 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J=9.2 Hz, 2H), 7.54 (d,J=7.6 Hz, 1H), 7.37-7.33 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 7.03 (d,J=8.8 Hz, 2H), 6.86 (s, 1H), 6.72 (dd, J=10.8, 17.2 Hz, 1H), 6.33 (dd,J=2.0, 17.2 Hz, 1H), 5.86 (d, J=11.6 Hz, 1H), 5.19 (s, 2H), 4.47 (br dd,J=3.6, 10.4 Hz, 4H). MS (ESI) m/z 508.3 [M+H]⁺10: Synthesized according to general procedure A starting fromintermediate III (800 mg, 1.88 mmol) obtained in 5, wherein in step A.3the OH nucleophile is 2-(1H-imidazol-1-yl)ethanol (632 mg, 5.64 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 1.5% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.71 (s,1H), 9.55 (br s, 1H), 8.87 (s, 1H), 8.60 (br d, J=4.4 Hz, 1H), 8.49 (s,1H), 7.99 (s, 1H), 7.89 (t, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.69 (br d,J=7.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.33 (s, 1H),7.29-7.17 (m, 2H), 6.87 (s, 1H), 6.73 (dd, J=10.2, 17.0 Hz, 1H), 6.35(br d, J=16.8 Hz, 1H), 5.88 (br d, J=11.2 Hz, 1H), 5.29 (s, 2H), 4.49(br s, 4H). MS (ESI) m/z 542.4 [M+H]⁺12: Synthesized according to general procedure A starting fromintermediate III (800 mg, 1.88 mmol) obtained in 4, wherein in step A.3the NH nucleophile is N-methyl-3-morpholinopropan-1-amine (595 mg, 3.76mmol); variant i) was used in step A.4; and variant i) was used in stepA.5; and 40% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.07 (s,1H), 8.84 (s, 1H), 8.67 (s, 1H), 8.64-8.58 (m, 1H), 7.92 (d, J=2.6 Hz,1H), 7.81-7.73 (m, 2H), 7.71-7.66 (m, 1H), 7.63 (s, 1H), 7.54 (dd,J=8.8, 2.6 Hz, 1H), 7.28-7.23 (m, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.57-6.49(m, 1H), 6.42-6.33 (m, 1H), 5.90 (dd, J=10.2, 1.0 Hz, 1H), 5.32 (s, 2H),3.70 (t, J=4.6 Hz, 4H), 3.09-3.02 (m, 2H), 2.79 (s, 3H), 2.47-2.36 (m,6H), 1.75 (br t, J=7.4 Hz, 2H). MS (ESI) m/z 588.4 [M+H]⁺13: To a solution from intermediate III (600 mg, 1.41 mmol, 1.00 eq)obtained in 4 in dimethylsulfoxide (20.0 mL) was added tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate (369 mg, 1.83 mmol, 1.30 eq)and potassium tert-butoxide (316 mg, 2.82 mmol, 2.00 eq). The mixturewas stirred at 25° C. for 12 h. The reaction mixture was diluted withwater (100 mL), filtered and the filter cake was concentrated underreduced pressure to give tert-butyl2-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(660 mg, crude) as a yellow solid, which was used into the next stepwithout further purification. To a solution of tert-butyl2-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(660 mg, 1.09 mmol, 1.00 eq) in dichloromethane (40.0 mL) and methanol(10.0 mL) was added nickel(ii) chloride hexahydrate (517 mg, 2.17 mmol,2.00 eq) and sodium borohydride (165 mg, 4.35 mmol, 4.00 eq). Themixture was stirred at 0° C. for 0.5 h. The reaction mixture wasconcentrated under reduced pressure to give a residue. To the residuewas added dichloromethane (20.0 mL) and the mixture was filtered. Thefiltrate was concentrated under reduced pressure to give tert-butyl2-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(500 mg, crude) as a yellow solid, which was used into the next stepwithout further purification. To a solution of tert-butyl2-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(300 mg, 520 umol, 1.00 eq) in dimethyl formamide (5.00 mL) was addedtriethylamine (105 mg, 1.04 mmol, 145 uL, 2.00 eq) and acrylic anhydride(98.3 mg, 780 umol, 1.50 eq). The mixture was stirred at 25° C. for 0.5h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to give a residue. The residue was purified byprep-HPLC to give tert-butyl2-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(140 mg, 222 umol, 43% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=9.62 (br s, 1H), 9.19 (s, 1H), 8.70-8.57 (m, 2H), 7.91 (d, J=2.6 Hz,1H), 7.82-7.74 (m, 1H), 7.71-7.66 (m, 1H), 7.62 (br s, 1H), 7.52 (dd,J=8.8, 2.6 Hz, 1H), 7.26 (br d, J=7.2 Hz, 1H), 7.14 (s, 1H), 7.02 (d,J=9.0 Hz, 1H), 6.88 (br dd, J=16.8, 10.2 Hz, 1H), 6.54 (d, J=16.0 Hz,1H), 5.83 (br d, J=10.4 Hz, 1H), 5.32 (s, 2H), 4.56 (br s, 1H),4.15-3.96 (m, 2H), 3.63-3.39 (m, 2H), 2.15-1.87 (m, 4H), 1.49 (s, 9H).MS (ESI) m/z 631.4 [M+H]⁺

To a solution of tert-butyl2-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)pyrrolidine-1-carboxylate(70.0 mg, 111 umol, 1.00 eq) in dichloromethane (1.0 mL) was added themixed solution of trifluoroacetic acid (152 mg, 1.33 mmol, 98.6 uL, 12.0eq) and dichloromethane (9.0 mL) dropwise. After addition, the mixturewas stirred at 25° C. for 1 h. The reaction mixture was concentratedunder reduced pressure to give a residue. The residue was purified byprep-HPLC to give 15 (24.36 mg, 38.3 umol, 35% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ=9.38 (br s, 1H), 9.01 (br s, 1H), 8.58 (br d,J=4.6 Hz, 1H), 8.36 (s, 2H), 7.77 (td, J=7.6, 1.4 Hz, 1H), 7.72-7.61 (m,2H), 7.42 (br d, J=8.4 Hz, 1H), 7.29-7.23 (m, 2H), 6.98 (s, 1H), 6.89(d, J=9.0 Hz, 1H), 6.49 (br dd, J=16.6, 10.2 Hz, 1H), 6.37-6.22 (m, 1H),5.52 (br d, J=10.4 Hz, 1H), 5.21 (s, 2H), 4.35-4.15 (m, 2H), 3.87 (br d,J=7.2 Hz, 1H), 3.37 (br d, J=7.4 Hz, 2H), 2.13 (br s, 2H), 2.06 (br d,J=7.4 Hz, 1H), 1.87-1.72 (m, 1H). MS (ESI) m/z 531.4 [M+H]⁺

14: Synthesized according to general procedure A starting fromintermediate III (800 mg, 1.88 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 1-methylpyrrolidin-2-yl)methanol (216 mg, 1.88mmol); variant i) was used in step A.4; and variant i) was used in stepA.5; and 7% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s,1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.60 (d, J=4.4 Hz, 1H), 8.49 (s, 1H),8.00 (d, J=2.4 Hz, 1H), 7.88 (dt, J=7.6, 2.0 Hz, 1H), 7.70 (dd, J=8.8,2.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.37 (dd, J=7.6, 5.6 Hz, 1H), 7.29(s, 1H), 7.25 (d, J=9.2 Hz, 1H), 6.63 (dd, J=17.2, 10.4 Hz, 1H), 6.30(dd, J=16.8, 1.6 Hz, 1H), 5.83-5.78 (m, 1H), 5.29 (s, 2H), 4.21-4.15 (m,1H), 4.12-4.06 (m, 1H), 2.99-2.94 (m, 1H), 2.71 (br dd, J=8.8, 6.0 Hz,1H), 2.38 (s, 3H), 2.25-2.18 (m, 1H), 2.03-1.95 (m, 1H), 1.73-1.65 (m,3H). MS (ESI) m/z 545.5 [M+H]⁺15: A mixture of III (600 mg, 1.41 mmol, 1.00 eq) obtained in 4tert-butyl 3-hydroxypyrrolidine-1-carboxylate (396 mg, 2.11 mmol, 1.50eq) and potassium tert-butoxide (316 mg, 2.82 mmol, 2.00 eq) indimethylsulfoxide (4.00 mL) was stirred at 25° C. for 1 h. The reactionmixture was quenched by addition of water (50.0 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine (3×50.0 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to give tert-butyl3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(900 mg, crude) as a yellow solid. To a mixture of tert-butyl3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(900 mg, 1.52 mmol, 1.00 eq) and nickel(ii) chloride hexahydrate (361mg, 1.52 mmol, 1.00 eq) in dichloromethane (10.0 mL) and methanol (10.0mL) was added sodium borohydride (115 mg, 3.04 mmol, 2.00 eq) at 25° C.The mixture was stirred at 25° C. for 0.5 h. The reaction mixture wasconcentrated to give a residue. The residue was dissolved indichloromethane (200 mL) and filtered. The filtrate was concentrated togive tert-butyl3-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(700 mg, crude) as yellow oil. To a solution of tert-butyl3-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(300 mg, 533 umol, 1.00 eq) and triethylamine (107 mg, 1.07 mmol, 2.00eq) in dimethyl formamide (3.00 mL) was added acrylic anhydride (67.2mg, 533 umol, 1.00 eq) at 25° C. The mixture was stirred at 25° C. for0.5 h. The reaction mixture was filtered. The filtrate was purified byprep-HPLC and lyophilized to give tert-butyl3-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(150 mg, 243 umol, 46% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=9.15 (s, 1H), 8.73-8.56 (m, 2H), 8.08 (br s, 1H), 7.90 (d, J=2.6 Hz,1H), 7.81-7.75 (m, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.57 (br s, 1H), 7.53(dd, J=8.8, 2.6 Hz, 1H), 7.27 (br s, 2H), 7.04 (d, J=8.8 Hz, 1H),6.60-6.44 (m, 1H), 6.42-6.23 (m, 1H), 5.90 (d, J=10.2 Hz, 1H), 5.33 (s,2H), 5.20 (br s, 1H), 4.02-3.46 (m, 4H), 2.46-2.23 (m, 2H), 1.50 (br s,9H). MS (ESI) m/z 617.4 [M+H]⁺

A mixture of tert-butyl3-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)pyrrolidine-1-carboxylate(70 mg, 113 umol, 1.00 eq), trifluoroacetic acid (308 mg, 2.70 mmol,23.8 eq) in dichloromethane (2.00 mL) was stirred at 25° C. for 2 h. Thereaction mixture was concentrated to give residue. The residue waspurified by prep-HPLC and lyophilized to give crude product. The crudeproduct was prep-HPLC and lyophilized to give 15 (2.91 mg, 5.63 umol, 5%yield, 100% purity) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.73(s, 1H), 9.57 (s, 1H), 8.99 (s, 1H), 8.61 (d, J=4.2 Hz, 1H), 8.50 (s,1H), 8.29 (br s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.90 (dt, J=7.8, 1.8 Hz,1H), 7.70 (dd, J=9.0, 2.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.39 (dd,J=6.6, 4.8 Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=9.2 Hz, 1H), 6.78 (dd,J=16.8, 10.2 Hz, 1H), 6.35 (dd, J=16.8, 2.0 Hz, 1H), 5.89-5.82 (m, 1H),5.38 (br s, 1H), 5.30 (s, 2H), 3.37 (br s, 4H), 2.31-2.16 (m, 2H). ¹HNMR (400 MHz, CDCl₃) δ=9.17 (s, 1H), 8.99 (s, 1H), 8.61 (s, 2H), 7.86(s, 1H), 7.83-7.75 (m, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.57-7.43 (m, 1H),7.28-7.26 (m, 1H), 7.01 (br d, J=9.2 Hz, 1H), 6.86-6.70 (m, 1H), 6.51(br d, J=16.4 Hz, 1H), 5.82 (br d, J=10.8 Hz, 1H), 5.37 (br s, 1H), 5.30(s, 2H), 3.86 (br d, J=13.2 Hz, 1H), 3.60 (br s, 1H), 3.48 (br d, J=10.8Hz, 2H), 2.51 (br s, 2H). MS (ESI) m/z 517.3 [M+H]⁺

16: Synthesized according to general procedure A starting fromintermediate III (700 mg, 1.64 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 1-methylpyrrolidin-3-ol (332 mg, 3.29 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 6% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.13 (s, 1H),8.81 (s, 1H), 8.64 (s, 1H), 8.62 (dd, J=4.2, 0.8 Hz, 1H), 7.90 (d, J=2.6Hz, 1H), 7.81-7.75 (m, 1H), 7.73 (s, 1H), 7.71-7.66 (m, 1H), 7.52 (dd,J=8.8, 2.6 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (s, 1H), 7.01 (d, J=8.8 Hz,1H), 6.58-6.38 (m, 2H), 5.89-5.76 (m, 1H), 5.31 (s, 2H), 5.07 (br s,1H), 3.18 (d, J=11.2 Hz, 1H), 3.11 (dt, J=8.4, 3.4 Hz, 1H), 2.66 (dd,J=11.2, 5.2 Hz, 1H), 2.60-2.48 (m, 1H), 2.46 (s, 3H), 2.37 (q, J=8.4 Hz,1H), 2.19-2.12 (m, 1H). MS (ESI) m/z 531.4 [M+H]⁺17: Synthesized according to general procedure A starting fromintermediate III (600 mg, 1.41 mmol) obtained in 4, wherein in step A.3the OH nucleophile is (R)-1-methylpyrrolidin-3-ol (285 mg, 2.82 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 9/6 overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.14 (s, 1H),8.64 (s, 1H), 8.61 (d, J=4.9 Hz, 1H), 8.52 (s, 1H), 7.89 (d, J=2.6 Hz,1H), 7.80-7.72 (m, 1H), 7.70-7.63 (m, 1H), 7.50 (dd, =2.6, 8.9 Hz, 1H),7.42 (s, 1H), 7.24 (br d, J=6.4 Hz, 1H), 7.17 (s, 1H), 7.02 (d, J=8.9Hz, 1H), 6.54-6.45 (m, 1H), 6.43-6.33 (m, 1H), 5.89-5.82 (m, 1H), 5.31(s, 2H), 5.10-5.01 (m, 1H), 3.15-2.99 (m, 2H), 2.72 (dd, J=5.5, 11.0 Hz,1H), 2.58-2.47 (m, 1H), 2.45 (s, 3H), 2.43-2.32 (m, 1H), 2.19-2.07 (m,1H). MS (ESI) m/z 531.2 [M+H]⁺18: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the OH nucleophile is (3S)-1-methylpyrrolidin-3-ol (237 mg, 2.34 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 33% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.14 (s, 1H),8.64 (s, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.55 (br s, 1H), 7.89 (d, J=2.8Hz, 1H), 7.80-7.74 (m, 1H), 7.70-7.65 (m, 1H), 7.52-7.48 (m, 1H), 7.41(s, 1H), 7.26-7.23 (m, 1H), 7.18 (s, 1H), 7.02 (d, J=8.8 Hz, 1H),6.56-6.46 (m, 1H), 6.44-6.34 (m, 1H), 5.89-5.82 (m, 1H), 5.31 (s, 2H),5.09-5.02 (m, 1H), 3.14-3.01 (m, 2H), 2.70-2.68 (m, 1H), 2.57-2.49 (m,1H), 2.45 (s, 3H), 2.40-2.37 (m, 1H), 2.17-2.11 (m, 1H). MS (ESI) m/z531.4 [M+H]⁺19: Synthesized according to general procedure A starting fromintermediate III (1.00 g, 2.35 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 2-(dimethylamino)ethanol (251 mg, 2.82 mmol);variant i) was used in step A.4; and variant i) was used in step A.5;and 21% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.67 (br d,J=10.4 Hz, 2H), 8.86 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.48 (s, 1H), 7.98(d, J=2.8 Hz, 1H), 7.88 (dt, J=7.6, 1.6 Hz, 1H), 7.69 (dd, J=8.8, 2.4Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.37 (dd, J=7.2, 4.8 Hz, 1H), 7.31 (s,1H), 7.25 (d, J=9.2 Hz, 1H), 6.67 (dd, J=17.2, 10.4 Hz, 1H), 6.31 (dd,J=17.2, 2.0 Hz, 1H), 5.84-5.79 (m, 1H), 5.29 (s, 2H), 4.30 (t, J=5.6 Hz,2H), 2.75 (t, 0.1=5.6 Hz, 2H), 2.25 (s, 6H). MS (ESI) m/z 519.4 [M+H]⁺20: Synthesized according to general procedure B, wherein in step B.1propane-1,3-diol (894 mg, 11.7 mmol) was used; in step B.2 variant i)was used, in step B.3 the nucleophile is2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.11 g, 8.21 mmol), instep B.4 variant i) was used and variant i) was used in step B.5; and 2%overall yield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.20-9.09 (m, 2H),8.57-8.51 (m, 2H), 8.42 (br s, 1H), 7.80 (d, 0.1=2.6 Hz, 1H), 7.72-7.67(m, 1H), 7.63 (br s, 1H), 7.61-7.56 (m, 1H), 7.42 (dd, J=8.8, 2.6 Hz,1H), 7.17 (br s, 1H), 6.93 (d, J=9.0 Hz, 1H), 6.87 (dd, J=17.0, 10.2 Hz,1H), 6.44 (dd, J=16.8, 1.2 Hz, 1H), 5.79-5.72 (m, 1H), 5.23 (s, 2H),4.50 (s, 1H), 4.19-4.13 (m, 3H), 3.95 (s, 1H), 3.74-3.68 (m, 1H),3.33-3.23 (m, 1H), 3.21-3.13 (m, 2H), 2.83 (br d, J=10.2 Hz, 1H), 2.19(br s, 2H), 2.07 (br d, J=10.8 Hz, 1H), 1.95 (br d, J=10.8 Hz, 1H). MS(ESI) m/z 587.4 [M+H]⁺21: Synthesized according to general procedure A starting fromintermediate III (700 mg, 1.64 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 3-morpholinopropan-1-ol (716 mg, 4.93 mmol);variant i) was used in step A.4, and variant i) was used in step A.5;and 18% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.67 (br s,1H), 9.59 (br s, 1H), 8.83 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.48 (s,1H), 7.99 (d, J=2.4 Hz, 1H), 7.88 (dt, J=8.0, 2.0 Hz, 1H), 7.69 (dd,J=8.8, 2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.37 (dd, J=7.2, 5.2 Hz,1H), 7.27-7.23 (m, 2H), 6.71 (dd, J=17.2, 10.4 Hz, 1H), 6.31 (dd,J=17.2, 2.0 Hz, 1H), 5.84-5.79 (m, 1H), 5.28 (s, 2H), 4.26 (t, J=6.0 Hz,2H), 3.58 (t, J=4.4 Hz, 4H), 2.48-2.45 (m, 2H), 2.38 (br s, 4H), 1.99(quin, 0.1=6.4 Hz, 2H). MS (ESI) m/z 575.4 [M+H]⁺22: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 3-pyrrolidin-1-ylpropan-1-ol (455 mg, 3.52 mmol);variant i) was used in step A.4; and variant i) was used in step A.5;and 15% overall yield from III. ¹H NMR (400 MHz, DMSO-4) δ=9.68 (s, 1H),9.60 (br s, 1H), 8.84 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.48 (s, 1H),8.22 (br s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.88 (dt, J=7.6, 1.6 Hz, 1H),7.69 (dd, J=8.8, 2.4 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.40-7.34 (m, 1H),7.28-7.22 (m, 2H), 6.72 (br dd, J=10.0, 15.6 Hz, 1H), 6.31 (dd, J=17.2,2.0 Hz, 1H), 5.85-5.78 (m, 1H), 5.28 (s, 2H), 4.26 (t, J=6.0 Hz, 2H),2.67-2.62 (m, 2H), 2.52 (br s, 4H), 2.05-1.99 (m, 2H), 1.71 (br s, 4H).MS (ESI) m/z 559.4 [M+H]⁺23: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-((6-(trifluoromethyl)pyridin-2-yl)methoxy)aniline(731 mg, 2.42 mmol); in step A.3 the OH nucleophile is2-morpholinoethanol (956 mg, 7.29 mmol); variant i) was used in stepA.4; and variant i) was used in step A.5; and 21% overall yield from II.¹H NMR (400 MHz, CDCl₃) δ=9.16 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H),8.40-8.30 (m, 1H), 8.01-7.92 (m, 2H), 7.90 (d, J=2.6 Hz, 1H), 7.67 (d,J=7.2 Hz, 1H), 7.63 (br s, 1H), 7.54 (dd, J=2.6, 8.8 Hz, 1H), 7.34 (s,1H), 7.01 (d, J=8.9 Hz, 1H), 6.61-6.39 (m, 2H), 6.02-5.81 (m, 1H), 5.37(s, 2H), 4.38 (t, J=5.5 Hz, 2H), 3.87-3.72 (m, 4H), 3.00 (t, J=5.5 Hz,2H), 2.76-2.62 (m, 4H). MS (ESI) m/z 629.3 [M+H]⁺24: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is3-chloro-4-((6-(trifluoromethoxy)pyridin-2-yl)methoxy)aniline (400 mg,1.26 mmol); in step A.3 the OH nucleophile 2-morpholinoethanol (324 mg,2.47 mmol); variant ii) was used in step A.4; and variant i) was used instep A.5; and 33% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆)δ=9.69 (s, 1H), 9.60 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H),8.12 (t, J=8.0 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.71 (dd, J=2.4, 9.2 Hz,1H), 7.63 (d, J=7.6 Hz, 1H), 7.34-7.24 (m, 3H), 6.68 (dd, J=10.4, 17.2Hz, 1H), 6.31 (dd, J=1.6, 17.2 Hz, 1H), 5.87-5.77 (m, 1H), 5.28 (s, 2H),4.34 (t, J=5.6 Hz, 2H), 3.60-3.53 (m, 4H), 2.82 (t, J=5.6 Hz, 2H). MS(ESI) m/z 645.2 [M+H]⁺25: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 1-methylazetidin-3-ol (580 mg, 4.70 mmol); varianti) was used in step A.4; and variant i) was used in step A.5; and 17%overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.05 (s, 1H), 8.56 (s,1H), 8.53 (d, J=4.9 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=2.6 Hz, 1H),7.72-7.66 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (dd,J=2.7, 8.8 Hz, 1H), 7.18 (br d, J=7.7 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H),6.87 (s, 1H), 6.52-6.40 (m, 1H), 6.34-6.24 (m, 1H), 5.89-5.79 (m, 1H),5.22 (s, 3H), 4.58-4.09 (m, 2H), 3.85-3.42 (m, 2H), 2.84 (s, 3H). MS(ESI) m/z 517.4 [M+H]⁺26: To a mixture of tert-butyl 2,5-dihydropyrrole-1-carboxylate (10.0 g,59.1 mmol, 1.00 eq) and rhodium acetate dimer (261 mg, 591 umol, 0.0100eq) in dichloromethane (100 mL) was added dropwise a solution of ethyl2-diazoacetate (10.1 g, 70.9 mmol, 1.20 eq) in dichloromethane (50.0 mL)within 1 h at 35° C. After addition, the mixture was stirred at 35° C.for 12 h. The mixture was concentrated to afford a residue. The residuewas distilled to remove the remained reactant under vacuum at 120° C.The distilled residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=1/0-10/1) to afford(1R,5S,6s)-3-tert-butyl 6-ethyl3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.60 g, 14.1 mmol, 24%yield) as a colorless oil and (1R,5S,6r)-3-tert-butyl 6-ethyl3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (1.90 g, 7.44 mmol, 13%yield) as a colorless oil. ¹H NMR (400 MHz, Chloroform-A) δ=4.12 (q,J=7.2 Hz, 2H), 3.73-3.53 (m, 2H), 3.46-3.35 (m, 2H), 2.05 (br s, 2H),1.47 (t, J=3.2 Hz, 1H), 1.44-1.39 (m, 9H), 1.25 (t, J=7.2 Hz, 3H). ¹HNMR (400 MHz, Chloroform-A)=4.09 (q, J=7.2 Hz, 2H), 3.84-3.69 (m, 2H),3.41 (br t, J=10.8 Hz, 2H), 1.86 (s, 1H), 1.84 (d, J=2.6 Hz, 1H),1.79-1.72 (m, 1H), 1.42 (s, 9H), 1.24 (t, J=7.1 Hz, 3H).

To a mixture of (1R,5S,6s)-3-tert-butyl 6-ethyl3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.10 g, 12.1 mmol, 1.00 eq)in methanol (20.0 mL) and water (20.0 mL) was added sodium hydroxide(1.46 g, 36.4 mmol, 3.00 eq) at 25° C. The mixture was stirred at 25° C.for 12 h. The mixture was concentrated to remove methanol, diluted withwater (50.0 mL), acidified with conc. hydrochloric to pH=4-5. Themixture was extracted with ethyl acetate (3×50.0 mL). The combinedorganic layers were washed with water (50.0 mL), dried over anhydroussodium sulfate, filtered and the filtrate was concentrated to afford(1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (2.40 g, 10.6 mmol, 87% yield) as a white solid. H NMR (400 MHz,Chloroform-A) δ=3.76-3.57 (m, 2H), 3.43 (br d, J=3.3 Hz, 2H), 2.13 (brs, 2H), 1.49 (t, J=3.0 Hz, 1H), 1.43 (s, 9H).

To a solution of(1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (2.40 g, 9.50 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was addeddropwise borane tetrahydrofuran complex (1.00 M, 19.0 mL, 2.00 eq) at 0°C. The mixture was stirred at 0° C. for 2 h. The reaction was quenchedwith methanol (5.00 mL) and concentrated to afford a residue. Theresidue was diluted sodium carbonate (10.0 mL), extracted with ethylacetate (2×20.0 mL). The combined organic layers were washed with water,dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated to afford (1R,5S,6s)-tert-butyl6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.00 g, 9.38mmol, 98% yield) as a colorless oil. ¹H NMR (400 MHz, Chloroform-A)δ=3.71-3.51 (m, 3H), 3.47 (br d, J=6.4 Hz, 1H), 3.35 (br t, J=8.3 Hz,2H), 1.49-1.29 (m, 12H), 0.95 (tt, J=3.4, 6.9 Hz, 1H).

To a solution of (1R,5S,6s)-tert-butyl6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.00 g, 9.38 mmol,1.00 eq) in dichloromethane (50.0 mL) was added Dess-Martin periodinane(4.38 g, 10.3 mmol, 3.19 mL, 1.10 eq) at 0° C. The mixture was stirredat 0° C. for 1 h. The mixture was diluted with water (5.00 mL) andsaturated sodium carbonate (5.00 mL), extracted with dichloromethane(2×20.0 mL). The combined organic layers were washed with water (20.0mL), dried over anhydrous sodium sulfate, filtered. The filtrate wasconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0-4/1) to afford(1R,5S,6s)-tert-butyl 6-formyl-3-azabicyclo[3.1.0] hexane-3-carboxylate(1.90 g, 8.99 mmol, 96% yield) as a colorless oil. ¹H NMR (400 MHz,Chloroform-d) δ=9.43 (d, J=4.0 Hz, 1H), 3.75-3.59 (m, 2H), 3.46 (br d,J=10.5 Hz, 2H), 2.21 (t, J=2.3 Hz, 2H), 1.82 (q, J=3.2 Hz, 1H), 1.44 (s,9H).

To a solution of (1R,5S,6s)-tert-butyl6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.90 g, 8.99 mmol,1.00 eq) and potassium carbonate (2.49 g, 18.0 mmol, 2.00 eq) inmethanol (40.0 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate(2.07 g, 10.8 mmol, 1.20 eq) at 20° C. The mixture was stirred at 20° C.for 12 h. The mixture was concentrated to dryness and diluted with ethylacetate (20.0 mL). After filtration, the filtrate was concentrated toafford a residue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=5/1) to afford (1R,5S,6r)-tert-butyl6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.20 g, 5.79 mmol,64% yield) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ=3.72-3.53(m, 2H), 3.34 (br t, J=7.6 Hz, 2H), 1.88 (d, J=2.1 Hz, 1H), 1.82 (t,J=2.8 Hz, 2H), 1.43 (s, 9H), 1.14-1.06 (m, 1H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(2.20 g, 4.76 mmol, 1.00 eq, hydrochloride) in dimethylformamide (25.0mL) was added potassium acetate (2.34 g, 23.8 mmol, 5.00 eq) at 15° C.The mixture was stirred at 100° C. for 1 h. The mixture was concentratedto afford a residue. The residue was diluted with water (30.0 mL). Afterfiltration, the filter cake was washed with water (10.0 mL), dried invacuum to afford 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-ol (2.00 g, 4.72 mmol, 99% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.06 (br s, 1H), 9.18 (s, 1H), 8.60(br d, J=4.3 Hz, 1H), 8.52 (s, 1H), 8.00 (d, J=2.1 Hz, 1H), 7.88 (dt,J=1.5, 7.6 Hz, 1H), 7.68 (br dd, J=2.0, 8.9 Hz, 1H), 7.58 (br d, J=7.8Hz, 1H), 7.37 (br dd, J=5.3, 6.7 Hz, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.17(s, 1H), 5.29 (s, 2H).

To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-ol(2.00 g, 4.72 mmol, 1.00 eq) and pyridine (1.87 g, 23.6 mmol, 1.90 mL,5.00 eq) in dichloromethane (60.0 mL) was added triflic anhydride (2.66g, 9.44 mmol, 1.56 mL, 2.00 eq) at 0° C. The mixture was stirred at 20°C. for 12 h. The mixture was concentrated to afford a residue. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=1/1-0/1) to afford 4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl trifluoromethanesulfonate (2.10 g,3.78 mmol, 80% yield) as a yellow solid.

To a solution of (1R,5S,6r)-tert-butyl6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.21 mmol,1.34 eq),4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoro-methanesulfonate (500 mg, 899 umol, 1.00 eq), copper iodide(34.3 mg, 180 umol, 0.200 eq) and triethylamine (6.06 g, 59.9 mmol, 8.33mL, 66.6 eq) in dimethylformamide (10.0 mL) was addedtetrakis[triphenylphosphine]palladium(0) (104 mg, 90.0 umol, 0.100 eq)at 15° C. The mixture was stirred at 15° C. for 12 h. The reaction wasconcentrated to afford a residue. The residue was triturated with ethylacetate (5.00 mL). After filtration, the filter cake was dried in vacuumto afford crude product. The crude product was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/1-0/1) to afford(1R,5S,6r)-tert-butyl6-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(450 mg, 587 umol, 65% yield, 80% purity) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ=10.31 (s, 1H), 9.39 (s, 1H), 8.67 (s, 1H), 8.60 (br d,J=4.3 Hz, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.93-7.81 (m, 2H), 7.70 (dd,J=2.5, 9.0 Hz, 1H), 7.60-7.57 (m, 1H), 7.37 (dd, J=5.1, 7.0 Hz, 1H),7.29 (d, J=9.0 Hz, 1H), 5.30 (s, 2H), 3.56 (br d, J=10.9 Hz, 2H),3.46-3.35 (m, 2H), 2.09 (br s, 2H), 1.47 (br t, J=3.3 Hz, 1H), 1.39 (s,9H). MS (ESI) m/z 613.4 [M+H]⁺

A mixture of (1R,5S,6r)-tert-butyl6-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(400 mg, 522 umol, 1.00 eq) in 4 M hydrochloride/ethyl acetate (3.00 mL)was stirred at 15° C. for 0.5 h. The mixture was concentrated to affordcrude product. The crude product was freed with saturated sodiumcarbonate (5.00 mL) and extracted with ethyl acetate (2×30 mL). Thecombined organic layers were washed with water (10.0 mL), dried overanhydrous sodium sulfate, filtered and concentrated to afford7-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(200 mg, 390 umol, 75% yield) as a yellow solid. MS (ESI) m/z 513.3[M+H]⁺

To a solution of7-((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-ylethynyl)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine (180 mg, 351 umol, 1.00 eq) andparaformaldehyde (52.7 mg, 1.75 mmol, 5.00 eq) in trifluoroethanol (5.00mL) was added sodium borohydride (26.6 mg, 702 umol, 2.00 eq) at 60° C.The mixture was stirred at 60° C. for 12 h. The mixture was concentratedto afford a residue. The residue was diluted with saturated sodiumcarbonate (1.00 mL) and water (5.00 mL), extracted with ethyl acetate(3-20 mL). The combined organic layer was washed with water (20.0 mL),dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-nitroquinazolin-4-amine(180 mg, 342 umol, 97% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=10.47 (s, 1H), 9.48 (s, 1H), 8.68 (s, 1H), 8.60 (br d, J=4.3Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.95 (s, 1H), 7.88 (dt, J=1.5, 7.7 Hz,1H), 7.72 (br dd, J=2.1, 9.0 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41-7.34(m, 1H), 7.29 (d, J=9.0 Hz, 1H), 5.30 (s, 2H), 3.69 (br d, J=11.2 Hz,2H), 3.40-3.36 (m, 2H), 2.76 (br s, 3H), 2.59 (br s, 1H), 2.31 (br s,2H). MS (ESI) m/z 527.4 [M+H]⁺

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-nitroquinazolin-4-amine (180 mg, 342 umol, 1 eq)and ammonium chloride (205 mg, 3.84 mmol, 134 uL, 11.3 eq) in methanol(10.0 mL) and water (10.0 mL) was added iron powder (167 mg, 2.99 mmol,8.75 eq) at 20° C. The mixture was heated to 80° C. and stirred at 80°C. for 1 h. The mixture was concentrated to afford a residue. Theresidue was diluted with water (10.0 mL), saturated sodium carbonate(5.00 mL), ethyl acetate (30.0 mL). The mixture was extracted with ethylacetate (2×30 mL) and the combined organic layer was washed with water(20.0 mL), dried over anhydrous sodium sulfate, filtered. The filtratewas concentrated to affordN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazoline-4,6-diamine(110 mg, 221 umol, 65% yield) as a brown solid.

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazoline-4,6-diamine (100 mg, 201 umol, 1.00 eq)and pyridine (0.500 M, 1.21 mL, 3.00 eq) in dimethylformamide (4.00 mL)was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(77.2 mg, 402 umol, 2.00 eq) and acrylic acid (0.100 M, 2.41 mL, 1.2 eq)at 0° C. The mixture was stirred at 15° C. for 5 h. The mixture wasfiltered to afford a solution. The solution was purified by prep-HPLCand lyophilized to afford 26 (35.5 mg, 63.8 umol, 32% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.83 (br d, J=3.5 Hz, 2H), 8.70 (s,1H), 8.60 (d, J=4.8 Hz, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 8.00 (d, J=2.4Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.76 (s, 1H), 7.70 (dd, J=2.4,8.9 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.2, 7.3 Hz, 1H), 7.26(d, J=9.0 Hz, 1H), 6.63 (dd, J=10.3, 17.0 Hz, 1H), 6.33 (dd, J=1.8, 17.0Hz, 1H), 5.85 (dd, J=1.7, 10.1 Hz, 1H), 5.29 (s, 2H), 3.01 (d, J=9.2 Hz,2H), 2.29 (br d, J=8.7 Hz, 2H), 2.23 (s, 3H), 1.95-1.86 (m, 3H). MS(ESI) m/z 551.0 [M+H]⁺

27: Synthesized according to general procedure A starting fromintermediate III (600 mg, 1.36 mmol) obtained in 1, wherein in step A.3the OH nucleophile is 2-morpholinoethanol (213 mg, 1.63 mmol); varianti) was used in step A.4; and variant ii) was used in step A.5; and 14%overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.08 (s, 1H), 8.65 (s,1H), 8.62 (s, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.73 (s, 1H), 7.48 (dd,J=8.8, 2.6 Hz, 1H), 7.36 (td, J=7.8, 6.2 Hz, 1H), 7.26-7.19 (m, 3H),7.08-6.99 (m, 1H), 6.91 (d, J=9.0 Hz, 1H), 6.52-6.31 (m, 2H), 5.84 (dd,J=9.8, 1.6 Hz, 1H), 5.22-5.05 (m, 2H), 4.31 (t, J=5.6 Hz, 2H), 3.83-3.70(m, 4H), 2.89 (t, J=5.6 Hz, 2H), 2.63-2.54 (m, 4H). MS (ESI) m/z 578.4[M+H]⁺28: Synthesized according to general procedure C, wherein in step C.1the diol is ethylene glycol (5.55 g, 89.4 mmol); in step C₁₋₃ H₂N—X is3-chloro-4-(2-pyridylmethoxy)aniline (842 mg, 3.59 mmol); in step C₁₋₄HNR′R″ is pyrrolidine (395 mg, 5.55 mmol); variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 7% overall yield from I.¹H NMR (400 MHz, DMSO-d₆) δ=9.70 (s, 1H), 9.64 (s, 1H), 8.85 (s, 1H),8.60 (d, J=4.0 Hz, 1H), 8.49 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.88 (dt,J=1.8, 7.7 Hz, 1H), 7.69 (dd, J=2.6, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz,1H), 7.37 (dd, J=5.0, 6.7 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=9.0 Hz, 1H),6.68 (dd, J=10.1, 17.1 Hz, 1H), 6.31 (dd, J=1.9, 17.1 Hz, 1H), 5.85-5.78(m, 1H), 5.29 (s, 2H), 4.32 (t, J=5.9 Hz, 2H), 2.92 (br t, J=5.6 Hz,2H), 2.57 (br s, 4H), 1.69 (br s, 4H). MS (ESI) m/z 545.4 [M+1]⁺29: Synthesized according to general procedure C starting fromintermediate XV (400 mg, 765 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 3-methoxypyrrolidine (211 mg, 1.53 mmol); variant ii) was usedin step C.5; and variant iii) was used in step C₁₋₆; and 6% overallyield from XV. ¹H NMR (400 MHz, MeOD-d₄) δ=8.89 (s, 1H), 8.56 (d, J=5.0Hz, 1H), 8.44 (s, 1H), 8.36 (br s, 1H), 7.95-7.87 (m, 2H), 7.72 (d,J=7.9 Hz, 1H), 7.57 (dd, J=2.6, 8.8 Hz, 1H), 7.39 (dd, J=5.2, 7.2 Hz,1H), 7.23 (s, 1H), 7.15 (d, J=8.9 Hz, 1H), 6.75-6.61 (m, 1H), 6.54-6.43(m, 1H), 5.87 (dd, J=1.6, 10.1 Hz, 1H), 5.27 (s, 2H), 4.47 (t, J=4.8 Hz,2H), 4.14 (br t, J=5.4 Hz, 1H), 3.55-3.39 (m, 2H), 3.33 (s, 3H),3.30-3.22 (m, 3H), 3.20-3.13 (m, 1H), 2.32-2.17 (m, 1H), 2.15-2.03 (m,1H).MS (ESI) m/z 575.1 [M+H]⁺30: Synthesized according to general procedure C starting fromintermediate XV (413 mg, 3.35 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is pyrrolidin-3-ol hydrochloride (413 mg, 3.35 mmol); variant ii)was used in step C.5; and variant i) was used in step C₁₋₆; and 20%overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s, 1H), 9.63(s, 1H), 8.86 (s, 1H), 8.60 (d, J=4.4 Hz, 1H), 8.48 (s, 1H), 7.98 (d,J=2.6 Hz, 1H), 7.91-7.85 (m, 1H), 7.69 (dd, J=2.4, 8.9 Hz, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.40-7.33 (m, 1H), 7.30 (s, 1H), 7.25 (d, J=9.0 Hz, 1H),6.69 (dd, J=10.5, 17.2 Hz, 1H), 6.31 (dd, J=1.8, 17.0 Hz, 1H), 5.81 (d,J=11.9 Hz, 1H), 5.29 (s, 2H), 4.69 (d, J=4.4 Hz, 1H), 4.30 (t, J=5.9 Hz,2H), 4.19 (br s, 1H), 2.93-2.88 (m, 2H), 2.82 (dd, J=6.1, 9.6 Hz, 1H),2.74-2.68 (m, 1H), 2.59-2.56 (m, 1H), 2.45-2.42 (m, 1H), 2.01-1.95 (m,1H), 1.59-1.48 (m, 1H). MS (ESI) m/z 561.0 [M+H]⁺31: Synthesized according to general procedure C starting fromintermediate XV (800 mg, 1.53 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (458 mg, 3.06mmol); variant ii) was used in step C.5; and variant ii) was used instep C₁₋₆; and 9% overall yield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.29(s, 1H), 9.19 (s, 1H), 8.66-8.58 (m, 2H), 8.51 (br s, 1H), 7.88 (d,1=2.6 Hz, 2H), 7.81-7.74 (m, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.52 (dd,J=8.8, 2.6 Hz, 1H), 7.32 (s, 1H), 7.27 (br d, J=7.0 Hz, 1H), 7.01 (d,J=9.0 Hz, 1H), 6.76-6.65 (m, 1H), 6.57-6.46 (m, 1H), 5.92-5.83 (m, 1H),5.31 (s, 2 H), 4.34 (t, J=5.4 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.62 (brd, J=9.8 Hz, 2H), 3.42 (br s, 2H), 3.13-3.10 (m, 2H), 2.17-1.99 (m, 4H).MS (ESI) m/z 587.4 [M+H]⁺32: Synthesized according to general procedure C starting fromintermediate XV (1.00 g, 1.91 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is N-methylethanamine (565 mg, 9.56 mmol); variant ii) was usedin step C.5; and variant i) was used in step C₁₋₆; and 4% overall yieldfrom XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 2H), 8.86 (s, 1H), 8.60(d, J=4.0 Hz, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.98 (d, J=2.6 Hz, 1H),7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.69 (dd, J=2.6, 8.9 Hz, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.37 (dd, J=5.0, 6.7 Hz, 1H), 7.30 (s, 1H), 7.25 (d,J=9.0 Hz, 1H), 6.68 (dd, J=10.3, 17.1 Hz, 1H), 6.31 (dd, J=1.8, 17.0 Hz,1H), 5.86-5.77 (m, 1H), 5.29 (s, 2H), 4.31 (t, J=5.7 Hz, 2H), 2.86 (t,J=5.7 Hz, 2H), 2.54-2.52 (m, 2H), 2.29 (s, 3H), 1.01 (t, J=7.2 Hz, 3H).MS (ESI) m/z 533.4 [M+1]⁺33: Synthesized according to general procedure C starting fromintermediate XV (150 mg, 308 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is azetidine (144 mg, 1.54 mmol) and the mixture was stirred at120° C. under microwave; variant ii) was used in step C.5; and variantii) was used in step C₁₋₆; and 49/6 overall yield from XV. ¹H NMR (400MHz, DMSO-d₆) δ=9.73-6.93 (m, 2H), 8.87 (s, 1H), 8.62-8.58 (m, 1H), 8.49(s, 1H), 8.18-8.13 (m, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.93-7.85 (m, 1H),7.72-7.66 (m, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.40-7.34 (m, 1H), 7.29-7.21(m, 2H), 6.67 (br d, J=9.6 Hz, 1H), 6.38-6.28 (m, 1H), 5.88-5.80 (m,1H), 5.29 (s, 2H), 4.30-4.20 (m, 2H), 3.60-3.50 (m, 4H), 3.15-3.10 (m,1H), 3.09-3.06 (m, 1H), 2.15-2.07 (m, 2H). MS (ESI) m/z 531.4 [M+H]⁺34: Synthesized according to general procedure C starting fromintermediate XV (800 mg, 1.53 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 3-fluoroazetidine hydrochloride (453 mg, 3.06 mmol), variantii) was used in step C.5; and variant iii) was used in step C₁₋₆; and 3%overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s, 1H), 9.61(s, 1H), 8.81 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.49 (s, 1H), 8.23 (s,1H), 7.99 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.69 (dd,J=2.6, 8.9 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 6.8 Hz,1H), 7.27-7.23 (m, 2H), 6.66 (dd, J=10.3, 16.9 Hz, 1H), 6.31 (dd, J=1.7,17.0 Hz, 1H), 5.84-5.79 (m, 1H), 5.29 (s, 2H), 5.23-5.05 (m, 1H), 4.21(br t, J=5.1 Hz, 2H), 3.69-3.60 (m, 2H), 3.31-3.19 (m, 2H), 2.93 (br t,J=5.1 Hz, 2H). MS (ESI) m/z 549.4 [M+1]⁺35: Synthesized according to general procedure C starting fromintermediate XV (500 mg, 956 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 3-methoxyazetidine hydrochloride (306 mg, 1.91 mmol); variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 6%overall yield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.13 (s, 1H), 8.93 (s,1H), 8.65 (s, 1H), 8.62 (d, 0.1=4.2 Hz, 1H), 7.90 (d, 1=2.6 Hz, 1H),7.82-7.74 (m, 1H), 7.71-7.66 (m, 1H), 7.56-7.48 (m, 2H), 7.28-7.24 (m,1H), 7.03 (d, J=8.8 Hz, 1H), 6.63-6.33 (m, 2H), 5.99-5.77 (m, 1H), 5.32(s, 2H), 4.24 (t, J=5.1 Hz, 2H), 4.11 (t, J=5.6 Hz, 1H), 3.74 (dd,J=6.2, 8.1 Hz, 2H), 3.31 (s, 3H), 3.14 (dd, J=5.6, 8.4 Hz, 2H), 3.01 (t,J=5.1 Hz, 2H). MS (ESI) m/z 561.1 [M+H]⁺36: Synthesized according to general procedure C starting fromintermediate XV (800 mg, 1.53 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (458 mg, 3.06mmol); variant ii) was used in step C.5; and variant i) was used in stepC₁₋₆; and 16% overall yield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.13 (s,1H), 8.66 (s, 1H), 8.62 (d, J=4.2 Hz, 1H), 8.28 (s, 1H), 7.90 (d, J=2.6Hz, 1H), 7.81-7.74 (m, 1H), 7.71-7.66 (m, 1H), 7.52 (dd, J=8.8, 2.6 Hz,1H), 7.43 (s, 1H), 7.28-7.24 (m, 2H), 7.03 (d, J=9.0 Hz, 1H), 6.56-6.48(m, 1H), 6.40-6.30 (m, 1H), 5.94-5.86 (m, 1H), 5.32 (s, 2H), 4.38-4.30(m, 4H), 2.90 (t, J=5.6 Hz, 2H), 2.68 (d, J=10.6 Hz, 2H), 2.53 (dd,J=10.8, 1.8 Hz, 2H), 1.97-1.88 (m, 4H). MS (ESI) m/z 587.3 [M+H]⁺37: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-(3-chlorophenoxy)aniline (965 mg, 4.39 mmol); in step A.3the OH nucleophile 2-morpholinoethanol (703 mg, 5.36 mmol); variant i)was used in step A.4; and variant i) was used in step A.5; and 26%overall yield from U. ¹H NMR (400 MHz, DMSO-d₆) δ=9.00 (s, 1H), 8.45 (s,1H), 8.23 (br s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.38-7.32 (m, 1H), 7.25(s, 1H), 7.14-7.08 (m, 3H), 7.03 (t, J=2.0 Hz, 1H), 6.98 (dd, J=8.2, 2.2Hz, 1H), 6.72 (dd, 1=17.0, 10.2 Hz, 1H), 6.51 (dd, J=17.0, 1.4 Hz, 1H),5.89 (dd, J=10.2, 1.6 Hz, 1H), 4.43 (t, J=5.0 Hz, 2H), 3.85-3.80 (m,4H), 3.06 (t, J=5.0 Hz, 2H), 2.75 (br s, 4H). MS (ESI) m/z 546.2 [M+H]⁺38: Synthesized according to general procedure C starting fromintermediate XV (800 mg, 1.53 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 2-oxa-6-azaspiro[3.3]heptane (607 mg, 6.12 mmol); variant ii)was used in step C.5; and variant i) was used in step C₁₋₆; and 18%overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 1H), 9.64(s, 1H), 8.82 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.49 (s, 1H), 8.24 (s,1H), 7.99 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.69 (dd,J=2.6, 9.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.37 (dd, J=5.3, 7.1 Hz,1H), 7.27-7.23 (m, 2H), 6.68 (dd, J=10.1, 17.0 Hz, 1H), 6.33 (dd, J=1.8,17.1 Hz, 1H), 5.86-5.80 (m, 1H), 5.29 (s, 2H), 4.58 (s, 4H), 4.17 (br t,J=5.3 Hz, 2H), 3.41 (s, 4H), 2.82 (br t, J=5.2 Hz, 2H). MS (ESI) m/z573.5 [M+1]⁺39: Synthesized according to general procedure C starting fromintermediate XV (0.400 g, 765 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 2-oxa-5-azabicyclo[2.2.1]heptane (279 mg, 2.06 mmol); variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 7%overall yield from XV. ¹H NMR (400 MHz, MeOD-d₄) δ=8.93 (s, 1H), 8.56(d, J=4.6 Hz, 1H), 8.42 (s, 1H), 7.95-7.86 (m, 2H), 7.72 (d, J=7.8 Hz,1H), 7.57 (dd, J=2.6, 8.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.20 (s, 1H), 7.15(d, J=8.9 Hz, 1H), 6.71-6.62 (m, 1H), 6.52-6.43 (m, 1H), 5.86 (dd,J=1.6, 10.3 Hz, 1H), 5.27 (s, 2H), 4.47 (s, 1H), 4.37-4.27 (m, 2H), 4.11(d, J=8.1 Hz, 1H), 3.72 (s, 1H), 3.68 (dd, J=1.5, 8.2 Hz, 1H), 3.25-3.16(m, 1H), 3.15-3.06 (m, 1H), 3.01 (d, J=9.3 Hz, 1H), 2.74 (d, J=10.5 Hz,1H), 1.98 (br d, J=9.4 Hz, 1H), 1.83 (br d, J=10.1 Hz, 1H). MS (ESI) m/z573.4 [M+H]⁺40: Synthesized according to general procedure C starting fromintermediate XV (600 mg, 1.15 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is N-methyltetrahydrofuran-3-amine (316 mg, 2.30 mmol); variantii) was used in step C.5; and variant ii) was used in step C₁₋₆; and 22%overall yield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.10 (d, J=1.8 Hz, 1H),8.90 (br s, 1H), 8.67-8.57 (m, 2H), 7.87-7.83 (m, 1H), 7.83-7.74 (m,2H), 7.67 (d, J=7.8 Hz, 1H), 7.52-7.44 (m, 1H), 7.24 (br s, 2H), 6.97(br s, 1H), 6.54-6.38 (m, 2H), 5.88-5.79 (m, 1H), 5.28 (d, J=2.6 Hz,2H), 4.32 (br d, J=4.0 Hz, 2H), 2.92 (br t, J=4.2 Hz, 2H), 3.11-2.74 (m,1H), 2.71-2.40 (m, 7H), 2.32 (s, 3H). MS (ESI) m/z 574.4 [M+H]⁺41: Synthesized according to general procedure C starting fromintermediate XV (600 mg, 1.15 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 1-methylpiperazine (230 mg, 2.30 mmol); variant ii) was usedin step C.5; and variant ii) was used in step C₁₋₆; and 22% overallyield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.12 (s, 1H), 8.65 (s, 2H),8.62 (d, J=4.4 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.82-7.74 (m, 1H),7.72-7.65 (m, 1H), 7.58 (s, 1H), 7.52 (dd, J=8.8, 2.6 Hz, 1H), 7.26 (brd, J=7.0 Hz, 1H), 7.03 (d, 1=9.0 Hz, 1H), 6.58-6.37 (m, 2H), 5.87 (dd,J=9.8, 1.4 Hz, 1H), 5.32 (s, 2H), 4.31 (t, J=5.4 Hz, 2H), 4.03 (td,J=8.6, 4.4 Hz, 1H), 3.93-3.85 (m, 1H), 3.84-3.71 (m, 2H), 3.33 (quin,J=6.6 Hz, 1H), 3.04-2.84 (m, 2H), 2.40 (s, 3H), 2.20-2.06 (m, 1H),1.99-1.88 (m, 1H). MS (ESI) m/z 575.4 [M+H]⁺42: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the NH nucleophile is 1-methylpiperazine (153 mg, 1.53 mmol); variant i)was used in step A.4; and variant ii) was used in step A.5; and 11%overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.06 (s, 1H), 8.75 (s,1H), 8.68 (s, 1H), 8.62 (d, J=4.2 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.77(dd, J=7.6, 1.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.63 (s, 1H), 7.59-7.49 (m,2H), 7.27 (br s, 1H), 7.03 (d, J=9.0 Hz, 1H), 6.55-6.47 (m, 1H),6.41-6.29 (m, 1H), 5.91 (d, J=10.8 Hz, 1H), 5.32 (s, 2H), 3.08 (t, J=4.8Hz, 4H), 2.69 (br s, 4H), 2.44 (s, 3H). MS (ESI) m/z 530.4 [M+H]⁺43: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the NH nucleophile is 1,4-diazabicyclo[3.2.1]octane hydrochloride (241mg, 1.62 mmol); variant i) was used in step A.4; and variant i) was usedin step A.5, and 1% overall yield from III. ¹H NMR (400 MHz, CD₃OD)δ=8.65 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48 (s, 1H), 8.44 (br s, 2H),7.96-7.90 (m, 2H), 7.74 (d, 1=8.0 Hz, 1H), 7.61 (dd, J=8.8, 2.4 Hz, 1H),7.44-7.40 (m, 1H), 7.38 (s, 1H), 7.18 (d, J=9.0 Hz, 1H), 6.69-6.59 (m,1H), 6.56-6.48 (m, 1H), 5.92 (d, J=11.4 Hz, 1H), 5.30 (s, 2H), 3.99 (brs, 1H), 3.63-3.53 (m, 1H), 3.39 (br d, J=11.00 Hz, 1H), 3.29-3.19 (m,3H), 3.19-3.14 (m, 1H), 3.12-3.00 (m, 2H), 2.24-2.05 (m, 2H). MS (ESI)m/z 542.4 [M+H]⁺44: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the NH nucleophile is 4-(azetidin-3-yl)morpholine (327 mg, 1.52 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 20% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=8.65-8.56 (m,2H), 8.47 (br s, 1H), 7.82-7.74 (m, 2H), 7.67 (br d, J=7.8 Hz, 2H), 7.48(br dd, J=8.8, 2.0 Hz, 2H), 7.26 (br d, J=6.8 Hz, 1H), 7.01-6.90 (m,2H), 6.57-6.47 (m, 1H), 6.34 (br dd, J=16.8, 10.2 Hz, 1H), 5.89 (br d,J=10.0 Hz, 1H), 5.30 (s, 2H), 4.06-3.97 (m, 2H), 3.84 (br s, 2H), 3.76(br t, J=4.2 Hz, 4H), 3.31-3.22 (m, 1H), 2.42 (br s, 4H). MS (ESI) m/z572.5 [M+H]⁺45: A mixture of intermediate III obtained in 4 (1.00 g, 2.35 mmol, 1.00eq), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (880 mg, 3.05mmol, 1.30 eq, oxalic acid salt) and potassium carbonate (974 mg, 7.05mmol, 3.00 eq) in dimethylsulfoxide (10.0 mL) was stirred at 25° C. for3 h. The reaction mixture was added water (20.0 mL). The mixture wasfiltered. The filter cake was dried to givetert-butyl6-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.5 g, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.02 (brs, 1H), 9.10 (s, 1H), 8.60 (br d, J=4.4 Hz, 1H), 8.46 (s, 1H), 8.00 (brd, J=1.8 Hz, 1H), 7.89 (br t, J=7.6 Hz, 1H), 7.68 (br d, J=8.8 Hz, 1H),7.59 (br d, J=7.8 Hz, 1H), 7.43-7.32 (m, 1H), 7.26 (br d, J=9.0 Hz, 1H),6.72 (s, 1H), 5.29 (s, 2H), 4.15 (s, 4H), 4.04 (br s, 4H), 1.39 (s, 9H).MS (ESI) m/z 604.2 [M+H]⁺

A mixture oftert-butyl6-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.40 g, 2.32 mmol, 1.00 eq) and trifluoroacetic acid (4.31 g, 37.8mmol, 2.80 mL, 16.3 eq) in dichloromethane (20.0 mL) was stirred at 25°C. for 4 h. The reaction mixture was concentrated to give a residue. Theresidue was triturated with ethyl acetate (10.0 mL) and petroleum ether(20.0 mL) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-4-amine(1.4 g, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.24 (s,1H), 8.80 (s, 1H), 8.62 (br d, J=4.3 Hz, 2H), 7.97-7.86 (m, 2H),7.64-7.55 (m, 2H), 7.41 (dd, J=5.1, 7.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H),6.82 (s, 1H), 5.35 (s, 2H), 4.30 (s, 4H), 4.20 (br t, J=5.9 Hz, 4H). MS(ESI) m/z 504.1 [M+H]⁺

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-4-amine(1.40 g, 2.78 mmol, 1.00 eq), formaldehyde (834 mg, 27.8 mmol, 765 uL,10.0 eq) and sodium borohydride (126 mg, 3.33 mmol, 1.20 eq) in1,1,1-trifluoroethane (10.0 mL) was stirred at 40° C. for 4 h. Thereaction mixture was concentrated to give a residue. The residue waspurified by Reverse-MPLC and concentrated under reduced pressure to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-6-nitroquinazolin-4-amine(600 mg, 1.16 mmol, 42% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.12 (s, 1H), 8.60 (d, J=4.3 Hz, 1H), 8.50 (s, 1H), 8.18 (s,2H), 8.02 (d, 0.1=2.3 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.71 (dd,J=2.3, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.38 (dd, J=5.0, 7.0 Hz,1H), 7.28 (d, J=9.0 Hz, 1H), 6.77 (s, 1H), 5.30 (s, 2H), 4.15 (s, 4H),3.85 (s, 4H), 2.53 (br s, 3H). MS (ESI) m/z 518.5 [M+H]⁺

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-6-nitroquinazolin-4-amine(600 mg, 1.16 mmol, 1.00 eq), iron (323 mg, 5.79 mmol, 5.00 eq) andammonium chloride (558 mg, 10.43 mmol, 364 uL, 9.00 eq) in methanol(15.0 mL) and water (2.00 mL) was stirred at 80° C. for 4 h. Thereaction mixture was added of methanol (100 mL). The mixture wasfiltered. The filtrate was concentrated to give a residue. The residuewas purified by prep-HPLC to give the mixture was filtered. The filtercake was dried to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)quinazoline-4,6-diamine(200 mg, 409 umol, 35% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.61 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 7.84 (d, J=2.3 Hz, 1H),7.82-7.71 (m, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.48 (dd, J=2.6, 8.8 Hz, 1H),7.26 (br d, J=6.8 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 6.93-6.81 (m, 3H),5.31 (s, 2H), 4.11 (s, 4H), 3.81 (br s, 2H), 3.43 (s, 4H), 2.36 (s, 3H).MS (ESI) m/z 488.3 [M+H]⁺

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)quinazoline-4,6-diamine(80.0 mg, 164 umol, 1.00 eq), triethylamine (49.8 mg, 492 umol, 68.5 uL,3.00 eq) in dimethyl formamide (2.00 mL) was added acrylic anhydride(20.7 mg, 164 umol, 1.41 uL, 1.00 eq) at 25° C. The mixture was stirredat 25° C. for 0.5 h. The reaction mixture was filtered. The filtrate waspurified by prep-HPLC and lyophilized to give 45 (4.15 mg, 7.50 umol,4.58% yield, 98% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.64-8.59 (m, 2H), 8.47 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.82-7.75 (m,2H), 7.68 (d, J=8.1 Hz, 1H), 7.50 (dd, =2.5, 8.7 Hz, 1H), 7.40 (br s,1H), 7.26 (br d, J=7.2 Hz, 1H), 7.07-6.93 (m, 2H), 6.59-6.49 (m, 1H),6.45-6.27 (m, 1H), 5.91 (br d, J=10.1 Hz, 1H), 5.30 (s, 2H), 4.07 (s,4H), 3.41 (s, 4H), 2.34 (s, 3H). MS (ESI) m/z 542.3 [M+H]⁺

46: Synthesized according to general procedure A starting fromintermediate III (400 mg, 939 umol) obtained in 4, wherein in step A.3the NH nucleophile is 2-methyl-2,7-diazaspiro[4.4]nonane (240 mg, 1.13mmol); variant ii) was used in step A.4; and variant ii) was used instep A.5; and 4% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.00(br s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.46 (br s, 3H), 8.26 (br s, 1H),7.81-7.71 (m, 2H), 7.65 (d, 1=7.8 Hz, 1H), 7.59 (br d, J=8.3 Hz, 1H),7.24 (br s, 1H), 7.01-6.96 (m, 1H), 6.94 (br s, 1H), 6.50 (br s, 2H),5.86 (br s, 1H), 5.28 (s, 2H), 3.62 (br d, J=8.8 Hz, 1H), 3.26-3.20 (m,4H), 3.11 (br d, J=7.1 Hz, 2H), 2.88 (br d, J=10.3 Hz, 1H), 2.70 (s,3H), 2.11-2.02 (m, 2H), 2.01-1.88 (m, 2H). MS (ESI) m/z 570.1 [M+H]⁺47: Synthesized according to general procedure A starting fromintermediate III (400 mg, 939 umol) obtained in 4, wherein in step A.3the NH nucleophile is 2-methyloctahydropyrrolo[3,4-c]pyrrole (243 mg,1.22 mmol); variant i) was used in step A.4; and variant ii) was used instep A.5; and 5% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆)δ=9.74 (s, 1H), 9.59 (s, 1H), 8.60 (d, J=4.4 Hz, 1H), 8.49-8.42 (m, 2H),8.01 (d, J=2.4 Hz, 1H), 7.92-7.85 (m, 1H), 7.71 (dd, J=2.4, 9.2 Hz, 1H),7.58 (d, J=8.0 Hz, 1H), 7.40-7.34 (m, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.07(s, 1H), 6.65-6.53 (m, 1H), 6.36-6.28 (m, 1H), 5.87-5.77 (m, 1H), 5.28(s, 2H), 3.47-3.38 (m, 2H), 3.07-2.99 (m, 2H), 2.86-2.81 (m, 2H), 2.24(s, 3H). MS (ESI) m/z 556.4 [M+H]⁺48: Synthesized according to general procedure A starting fromintermediate III (600 mg, 1.41 mmol) obtained in 4, wherein in step A.3the NH nucleophile is N,1-dimethylpyrrolidin-3-amine (241 mg, 2.11mmol); variant ii) was used in step A.4; and variant ii) was used instep A.5; and 19/o overall yield from III. ¹H NMR (400 MHz, DMSO-d₆)δ=9.66 (br d, J=7.1 Hz, 2H), 8.70 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.47(s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.5, 7.7 Hz, 1H), 7.70 (dd,J=2.4, 8.9 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.37 (dd, J=5.3, 7.0 Hz,1H), 7.33 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.69 (br dd, J=10.3, 16.9 Hz,1H), 6.33 (dd, J=1.7, 16.9 Hz, 1H), 5.82 (br d, J=11.7 Hz, 1H), 5.28 (s,2H), 3.90 (br s, 1H), 2.72 (s, 3H), 2.63 (br dd, J=4.2, 9.5 Hz, 2H),2.44 (br s, 1H), 2.31-2.26 (m, 1H), 2.23 (s, 3H), 1.99-1.79 (m, 2H). MS(ESI) m/z 544.4 [M+H]⁺ 566.4 [M+Na]⁺49: Synthesized according to general procedure A starting fromintermediate III (500 mg, 1.17 mmol) obtained in 4, wherein in step A.3the NH nucleophile is 1-methyloctahydropyrrolo[3,4-b]pyrrole (178 mg,1.41 mmol); variant i) was used in step A.4; and variant ii) was used instep A.5; and 23% overall yield from III. ¹H NMR (400 MHz, CD₃OD) δ=8.58(br s, 2H), 8.44 (s, 1H), 7.97-7.90 (m, 2H), 7.74 (d, J=7.8 Hz, 1H),7.60 (dd, J=9.0, 2.2 Hz, 1H), 7.45-7.37 (m, 1H), 7.29 (s, 1H), 7.18 (d,J=9.0 Hz, 1H), 6.73-6.62 (m, 1H), 6.58-6.49 (m, 1H) 5.91 (d, J=10.0 Hz,1H), 5.30 (s, 2H), 3.58 (d, J=10.4 Hz, 1H), 3.28 (br d, J=9.0 Hz, 1H)3.18-3.12 (m, 1H), 3.07-2.96 (m, 3H), 2.88 (br dd, J=10.0, 4.0 Hz, 1H),2.50 (s, 3H), 2.44-2.36 (m, 1H), 2.34-2.24 (m, 1H), 1.82-1.70 (m, 1H).MS (ESI) m/z 556.4 [M+H]⁺50: To a mixture of intermediate III obtained in 4 (400 mg, 939 umol,1.00 eq) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (205mg, 1.03 mmol, 1.10 eq, 0.5 oxalic acid) in acetonitrile (10.0 mL) wasadded potassium carbonate (260 mg, 1.88 mmol, 2.00 eq) The mixture wasstirred at 80° C. for 2 h. After the reaction was completed, the mixturewas filtered. The filter cake was washed with ethyl acetate (50 mL). Thefiltrate was combined and concentrated to givetert-butyl6-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate(511 mg, crude) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.75-8.60(m, 2H), 8.54 (s, 1H), 8.41 (s, 1H), 7.85-7.70 (m, 5H), 7.11 (d, 1=8.4Hz, 1H), 6.68 (s, 1H), 5.33 (s, 2H), 4.55-4.50 (m, 2H), 4.43-4.42 (m,2H), 3.95-3.85 (m, 2H), 2.65-2.50 (m, 2H), 1.40 (s, 9H).

A solution of tert-butyl6-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate(490 mg, 811 umol, 1.00 eq) in a mixture solvent of trifluoroacetic acid(0.500 mL) and dichloromethane (5.00 mL) was stirred at 10° C. for 1 h.Then the mixture was stirred at 20° C. for 2 h. To the mixture was addedtrifluoroacetic acid (0.500 mL) and the mixture was stirred at 20° C.for 4 h. After the reaction was completed, the mixture was concentratedto giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(1,6-diazaspiro[3.3]heptan-6-yl)quinazolin-4-amine(510 mg, crude, trifluoroacetate) as a yellow oil.

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(1,6-diazaspiro[3.3]heptan-6-yl)quinazoline-4-amine (500 mg, 809 umol, 1.00 eq, trifluoroacetate),sodium borohydride acetate (343 mg, 1.62 mmol, 2.00 eq) and formalinsolution (98.5 mg, 1.21 mmol, 28% purity, 1.50 eq) in acetonitrile (5.00mL) was stirred at 25° C. for 10 h. After the reaction was completed,the mixture was concentrated to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)-6-nitroquinazolin-4-amine(821 mg, crude) as a yellow oil.

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)-6-nitroquinazolin-4-amine(815 mg, crude), iron powder (308 mg, 5.51 mmol, 3.50 eq) and ammoniumchloride (295 mg, 5.51 mmol, 3.50 eq) in a mixture solvent of methanol(5.00 mL) and water (3.00 mL) was stirred at 80° C. for 1 h. After thereaction was completed, the mixture was concentrated to remove water andgive a residue. The residue was triturated with methanol (30.0 mL) andfiltered. The pH of the filtrate was adjusted to around 11 and solidprecipitated in the mixture. The volume of the mixture was concentratedto about 5.00 mL. The mixture was filtered and the filtrate was purifiedby prep-HPLC to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)quinazoline-4,6-diamine(46.0 mg, 94.3 umol, 6% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=8.60 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 7.83 (d,J=2.4 Hz, 1H), 7.79-7.72 (m, 1H), 7.66 (d, 0.1=8.0 Hz, 1H), 7.47 (dd,J=2.4, 8.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.95 (s,1H), 6.91 (br s, 1H), 6.87 (s, 1H), 5.29 (s, 2H), 4.18-4.10 (m, 2H),4.06-4.00 (m, 2H), 3.84 (br s, 2H), 3.21 (t, 0.1=6.8 Hz, 2H), 2.45 (t,J=6.8 Hz, 2H), 2.37 (s, 3H).

A mixture ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)quinazoline-4,6-diamine (29.0 mg, 59.4 umol, 1.00 eq), acrylic acid(5.14 mg, 71.3 umol, 1.20 eq), pyridine (14.1 mg, 178 umol, 3.00 eq) andcarbon diylamine hydrochloride (17.1 mg, 89.1 umol, 1.50 eq) in dimethylformamide (0.500 mL) was stirred at 15° C. for 1 h. After the reactionwas completed, the mixture was filtered and the filtrate was purified byprep-HPLC to give 50 (19.03 mg, 34.76 umol, 58% yield, 99% purity) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.62 (s, 1H), 8.61 (br d, J=4.4Hz, 1H), 8.57 (br s, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.80-7.72 (m, 1H),7.70-7.64 (m, 1H), 7.49 (dd, J=2.4, 8.8 Hz, 1H), 7.46-7.35 (m, 2H),7.26-7.22 (m, 1H), 7.08 (s, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.57-6.48 (m,1H), 6.40-6.27 (m, 1H), 5.90 (br d, J=10.0 Hz, 1H), 5.30 (s, 2H),4.17-4.10 (m, 2H), 4.02-3.94 (m, 2H), 3.21 (t, J=6.8 Hz, 2H), 2.45 (t,J=6.8 Hz, 2H), 2.37 (s, 3H). MS (ESI) m/z 542.4 [M+H]⁺

51: Synthesized according to general procedure C starting fromintermediate XV (430 mg, 822 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is hexahydro-1H-furo[3,4-c]pyrrole (0.100 g, 884 umol); variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 47%overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=8.92 (s, 1H), 8.56(d, J=4.5 Hz, 1H), 8.45 (s, 1H), 8.28 (br s, 1H), 7.95-7.87 (m, 2H),7.72 (d, J=7.9 Hz, 1H), 7.59 (dd, J=2.6, 8.8 Hz, 1H), 7.44-7.36 (m, 1H),7.24 (s, 1H), 7.17 (d, J=8.9 Hz, 1H), 6.72-6.63 (m, 1H), 6.54-6.44 (m,1H), 5.88 (dd, J=1.6, 10.1 Hz, 1H), 5.28 (s, 2H), 4.43 (t, J=4.8 Hz,2H), 3.78 (d, J=9.2 Hz, 2H), 3.69-3.60 (m, 2H), 3.46-3.38 (m, 2H), 3.25(br d, J=4.8 Hz, 1H), 3.03 (br s, 2H), 2.55 (br dd, J=5.7, 10.2 Hz, 2H).MS (ESI) m/z 587.3 [M+H]⁺52: Synthesized according to general procedure C starting fromintermediate XV (500 mg, 956 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 1-oxa-6-azaspiro[3.3]heptane oxalate (235 mg, 1.24 mmol);variant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 7% overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 1H),9.63 (s, 1H), 8.84 (s, 1H), 8.61 (d, J=4.2 Hz, 1H), 8.50 (s, 1H), 8.34(s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd,J=2.5, 9.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.38 (dd, J=5.2, 6.8 Hz,1H), 7.26 (t, J=4.5 Hz, 2H), 6.70 (dd, J=10.1, 17.0 Hz, 1H), 6.34 (dd,J=1.8, 16.9 Hz, 1H), 5.96-5.72 (m, 1H), 5.29 (s, 2H), 4.36 (t, J=7.5 Hz,2H), 4.19 (br t, J=5.3 Hz, 2H), 3.64-3.55 (m, 2H), 3.26-3.17 (m, 2H),2.85 (br t, J=5.3 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H). MS (ESI) m/z 573.1.1[M+H]⁺53: Synthesized according to general procedure C starting fromintermediate XV (600 mg, 1.15 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is N-methylcyclopropanamine (247 mg, 2.30 mmol); variant ii) wasused in step C.5; and variant i) was used in step C₁₋₆; and 19/o overallyield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s, 1H), 9.56 (s, 1H),8.83 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.63-8.58 (m, 1H), 8.49 (s, 1H),7.99 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.69 (dd, J=2.5,9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 7.1 Hz, 1H), 7.29(s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.66 (dd, J=10.3, 17.0 Hz, 1H), 6.30(dd, J=1.7, 17.0 Hz, 1H), 5.81 (dd, 1=1.7, 10.1 Hz, 1H), 5.29 (s, 2H),4.31 (t, J=5.9 Hz, 2H), 3.00 (t, J=5.8 Hz, 2H), 2.37 (s, 3H), 1.81 (tt,J=3.4, 6.5 Hz, 1H), 0.46-0.40 (m, 2H), 0.36-0.30 (m, 2H). MS (ESI) m/z545.4 [M+H]⁺54: A solution of tert-butyl(1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate (1.40 g, 2.36 mmol, 1.00 eq) inhydrochloric acid/ethyl acetate (4M, 20.0 mL) was stirred at 15° C. for2 h under nitrogen atmosphere. The mixture was filtered. The filter cakewas washed ethyl acetate (3×3.00 mL) and dried under reduced pressure toafford7-((1-aminocyclopropyl)methoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(1.00 g, 1.89 mmol, 80% yield, hydrochloride) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=12.09 (br s, 1H), 9.97-9.73 (m, 1H), 8.94 (br d,J=1.5 Hz, 1H), 8.86 (br s, 2H), 8.73 (br d, J=4.6 Hz, 1H), 8.27-8.09 (m,1H), 7.96 (d, J=2.4 Hz, 1H), 7.78 (br d, J=7.3 Hz, 1H), 7.75-7.68 (m,2H), 7.60 (br d, J=4.9 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 5.55-5.40 (m,2H), 4.53 (s, 2H), 1.32-1.17 (m, 2H), 1.13-1.04 (m, 2H).

To a solution of7-((1-aminocyclopropyl)methoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(1.00 g, 1.89 mmol, 1.00 eq, hydrochloride) in acetonitrile (25.0 mL)was added 37% formalin (460 mg, 5.67 mmol, 422 uL, 3.00 eq), sodiumtriacetoxy borohydride (1.28 g, 6.04 mmol, 3.20 eq). The mixture wasstirred at 25° C. for 12 h. The mixture was concentrated under reducedpressure to give a residue. The residue was triturated with water (10.0mL) and dried under reduced pressure to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(dimethylamino)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine(650 mg, 998 umol, 52% yield, 80% purity) as a yellow solid. ¹H NMR (400MHz, CD₃OD) δ=9.05 (br s, 1H), 8.56 (br s, 2H), 7.98-7.86 (m, 3H), 7.71(br d, J=7.8 Hz, 1H), 7.60 (br d, J=7.8 Hz, 1H), 7.40 (br d, J=6.4 Hz,1H), 7.33 (s, 1H), 7.16 (br d, J=8.6 Hz, 1H), 5.27 (s, 2H), 4.52 (br s,2H), 2.96-2.80 (m, 6H), 1.17 (br d, J=13.2 Hz, 4H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(dimethylamino)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine(650 mg, 998 umol, 80% purity, 1.00 eq) in a mixture solvent of methanol(18.0 mL) and water (9.00 mL) was added iron powder (502 mg, 8.98 mmol,9.00 eq) and ammonium chloride (374 mg, 6.99 mmol, 7.00 eq). The themixture was stirred at 60° C. for 12 h. The mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase chromatography and lyophilized to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(dimethylamino)cyclopropyl)methoxy)quinazoline-4,6-diamine (180 mg, 319 umol, 31% yield, 87%purity) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ=8.56 (d, J=4.9 Hz,1H), 8.29 (s, 1H), 7.92 (dt, J=1.7, 7.8 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),7.73 (d, J=7.8 Hz, 1H), 7.54 (dd, J=2.4, 8.8 Hz, 1H), 7.44-7.38 (m, 1H),7.36 (s, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 5.28 (s, 2H), 4.26(s, 2H), 2.56 (s, 6H), 0.92-0.82 (m, 4H).

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(dimethylamino)cyclopropyl)methoxy)quinazoline-4,6-diamine (160 mg, 284 umol, 87% purity, 0.87 eq)in dimethylformamide (0.400 mL) was added acrylic acid (0.500 M indimethylformamide, 977 uL, 1.50 eq), carbodiimide hydrochloride (125 mg,652 umol, 2.00 eq) and pyridine (0.500 M in dimethylformamide, 1.30 mL,2 eq). The mixture was stirred at 25° C. for 2 h. After the reaction wascompleted, the mixture was filtered. The filtrate was purified byprep-HPLC and lyophilized to afford 54 (85.18 mg, 148.16 umol, 45%yield, 94% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=9.09 (s,1H), 8.64 (s, 1H), 8.61 (br d, J=3.4 Hz, 1H), 8.28 (s, 1H), 7.89 (d,J=2.4 Hz, 1H), 7.81-7.73 (m, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.54-7.47 (m,2H), 7.25 (br d, J=7.3 Hz, 1H), 7.21 (s, 1H), 7.06-6.99 (m, 1H), 6.49(d, J=16.9 Hz, 1H), 6.34-6.21 (m, 1H), 5.96-5.84 (m, 1H), 5.31 (s, 2H),4.22 (s, 2H), 2.57 (s, 6H), 0.98-0.86 (m, 2H), 0.83-0.74 (m, 2H). MS(ESI) m/z 545.5 [M+H]⁺

55: To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate(1.00 g, 5.34 mmol, 3.00 eq) in tetrahydrofuran (30.0 mL) was addedsodium hydride (427 mg, 10.7 mmol, 60% purity, 6.00 eq) at 0° C. and themixture was stirred at 0° C. for 0.5 h.N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(758 mg, 1.78 mmol, 1.00 eq) was added to the reaction mixture. Theresult solution was stirred at 50° C. for 2.5 h. The mixture was dilutedwith ethyl acetate (180 mL). The combined organic layers were washedwith brine (6×15.0 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford tert-butyl(1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate(1.40 g, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.14 (brs, 1H), 9.31-9.13 (m, 1H), 8.60 (br d, J=4.6 Hz, 1H), 8.56 (s, 1H), 7.98(br d, J=2.4 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.80-7.62 (m, 3H),7.58 (br d, J=7.8 Hz, 1H), 7.43-7.33 (m, 2H), 7.26 (br d, J=9.0 Hz, 2H),5.29 (s, 2H), 4.26 (s, 2H), 1.36 (br d, J=2.0 Hz, 9H), 0.76 (br s, 2H),0.71-0.68 (m, 2H).

To a solution of tert-butyl(1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate (1.00 g, 1.69 mmol, 1.00 eq) inmethanol (44.0 mL) was added iron powder (848 mg, 15.1 mmol, 9.00 eq),ammonium chloride (631 mg, 11.8 mmol, 7.00 eq) and water (11.0 mL). Thethe mixture was stirred at 60° C. for 12 h. The mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed phase chromatography and lyophilized to givetert-butyl(1-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate(300 mg, 533 mmol, 31% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.23 (s, 1H), 8.68-8.53 (m, 1H), 8.30 (s, 1H), 8.05 (d, J=2.4Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd, J=2.6, 8.9 Hz, 1H),7.58 (d, J=7.8 Hz, 1H), 7.52 (br s, 1H), 7.39-7.36 (m, 1H), 7.35 (s,1H), 7.22 (d, J=9.0 Hz, 1H), 6.95 (s, 1H), 5.51 (br s, 2H), 5.27 (s,2H), 4.02 (s, 2H), 1.37 (s, 9H), 0.89-0.82 (m, 2H), 0.82-0.77 (m, 2H)

To a solution of tert-butyl(1-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate (280 mg, 497 umol, 1.00 eq) indimethylformamide (0.500 mL) was added carbodiimide hydrochloride (191mg, 995 umol, 2.00 eq), acrylic acid (0.500 M in dimethylformamide, 1.49mL, 1.50 eq) and pyridine (0.500 M in dimethylformamide, 1.99 mL, 2.00eq). The mixture was stirred at 25° C. for 12 h. After the reaction wascompleted, the mixture was filtered. The filtrate was purified byprep-HPLC and lyophilized to afford tert-butyl(1-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate (150 mg, 243 umol, 48%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.70 (s, 1H), 9.46(br s, 1H), 9.12 (br s, 1H), 8.60 (d, J=3.9 Hz, 1H), 8.46 (s, 1H), 7.96(d, 1=2.7 Hz, 1H), 7.88 (dt, J1=1.7, 7.7 Hz, 1H), 7.67 (dd, J=2.6, 8.9Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.55 (br s, 1H), 7.37 (dd, J=5.5, 7.2Hz, 1H), 7.24 (d, J=9.0 Hz, 1H), 7.17 (s, 1H), 6.81 (br dd, J=10.0, 16.9Hz, 1H), 6.39 (br d, J=16.6 Hz, 1H), 5.93-5.83 (m, 1H), 5.29 (s, 2H),4.15 (s, 2H), 1.37 (s, 9H), 0.95-0.87 (m, 2H), 0.84 (br s, 2H).

To a solution of tert-butyl(1-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)cyclopropyl)carbamate(10.0 mg, 16.2 umol, 1.00 eq) in dichloromethane (1.00 mL) was addedtrifluoroacetic acid (154 mg, 1.35 mmol, 0.100 mL, 83.3 eq). The mixturewas stirred at 25° C. for 2 h. The mixture was concentrated underreduced pressure to give a residue. The residue was combined with theresidue of EW8418-290 and purified by prep-HPLC and lyophilized toafford 55 (5.74 mg, 4.37 umol, 26% yield, 96% purity, trifluoroacetate)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.85 (br s, 1H), 9.76(s, 1H), 9.20 (s, 1H), 8.75 (s, 1H), 8.67 (br s, 3H), 8.61 (br d, J=3.7Hz, 1H), 7.94-7.85 (m, 2H), 7.60 (br d, J=7.8 Hz, 2H), 7.43-7.36 (m,1H), 7.36-7.29 (m, 2H), 6.79 (dd, J=10.3, 16.9 Hz, 1H), 6.40 (d, J=17.1Hz, 1H), 5.97-5.87 (m, 1H), 5.35-5.30 (m, 2H), 4.38 (s, 2H), 1.14 (s,2H), 1.10-1.03 (m, 2H). MS (ESI) m/z 517.2 [M+H]⁺

56: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 2-fluoro-4-(pyridin-2-ylmethoxy)aniline (1.44 g, 6.59 mmol);in step A.3 the OH nucleophile 2-morpholinoethanol (250 mg, 1.91 mmol);variant ii) was used in step A.4; and variant ii) was used in step A.5;and 24% overall yield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.17 (s, 1H),8.69-8.58 (m, 3H), 8.09-7.96 (m, 1H), 7.76 (td, J=7.8, 1.8 Hz, 1H), 7.54(d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.28-7.24 (m, 1H),6.94-6.83 (m, 2H), 6.58-6.35 (m, 2H), 5.87 (dd, J=10.0, 1.4 Hz, 1H),5.24 (s, 2H), 4.37 (t, J=5.6 Hz, 2H), 3.85-3.72 (m, 4H), 2.93 (t, J=5.6Hz, 2H), 2.68-2.58 (m, 4H). MS (ESI) m/z 545.3 [M+H]⁺57: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 5-chloro-2-fluoro-4-(pyridin-2-ylmethoxy)aniline (1.11 g,4.39 mmol); in step A.3 the OH nucleophile 2-morpholinoethanol (399 mg,3.04 mmol); variant ii) was used in step A.4; and variant i) was used instep A.5, and 9% overall yield from II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.66(br s, 1H), 9.59 (s, 1H), 8.85 (s, 1H), 8.66-8.58 (m, 1H), 8.39 (s, 1H),7.91 (td, J=7.6, 1.8 Hz, 1H), 7.61 (dd, J=8.0, 3.6 Hz, 2H), 7.40 (dd,J=7.4, 5.8 Hz, 1H), 7.36 (d, J=11.8 Hz, 1H), 7.32 (s, 1H), 6.70 (dd,J=17.0, 10.2 Hz, 1H), 6.31 (dd, J=17.0, 1.8 Hz, 1H), 5.82 (dd, J=10.2,1.8 Hz, 1H), 5.34 (s, 2H), 4.35 (t, J=5.8 Hz, 2H), 3.65-3.51 (m, 4H),2.84 (t, J=5.8 Hz, 2H), 2.56-2.52 (m, 4H). MS (ESI) m/z 579.3 [M+H]⁺58: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 5-(pyridin-2-ylmethoxy)pyridin-2-amine (305 mg, 1.52 mmol);in step A.3 the OH nucleophile 2-morpholinoethanol (241 mg, 1.84 mmol);variant i) was used in step A.4; and variant i) was used in step A.5;and 1% overall yield from II. ¹H NMR (400 MHz, CD₃OD) δ=8.99 (s, 1H),8.58 (br d, J=4.2 Hz, 1H), 8.48 (s, 1H), 8.44 (br s, 2H) 8.24-8.13 (m,2H), 7.91 (td, J=7.8, 1.8 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.54 (dd,J=9.0, 2.8 Hz, 1H), 7.41 (dd, J=6.8, 5.0 Hz, 1H), 7.22 (s, 1H), 6.70(dd, J=17.0, 10.2 Hz, 1H), 6.48 (dd, J=17.0, 1.6 Hz, 1H), 5.90-5.82 (m,1H), 5.27 (s, 2H), 4.39 (br t, J=5.0 Hz, 2H), 3.84-3.76 (m, 4H), 3.00(t, J=5.0 Hz, 2H), 2.69 (br s, 4H). MS (ESI) m/z 528.4 [M+H]⁺59: Synthesized according to general procedure A starting fromintermediate III (600 mg, 1.47 mmol) obtained in 56, wherein in step A.3the NH nucleophile is 1-methylpyrrolidin-3-ol (297 mg, 2.93 mmol);variant ii) was used in step A.4; and variant iii) was used in step A.5;and 19% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.54 (br d,J=13.7 Hz, 2H), 8.86 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 7.86(dt, J=1.8, 7.7 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.40-7.29 (m, 2H), 7.12(s, 1H), 7.04 (dd, J=2.4, 12.0 Hz, 1H), 6.90 (dd, J=2.0, 8.7 Hz, 1H),6.74 (dd, J=10.2, 17.1 Hz, 1H), 6.30 (dd, J=1.9, 17.1 Hz, 1H), 5.86-5.74(m, 1H), 5.22 (s, 2H), 5.10 (br s, 1H), 2.82 (br d, J=3.7 Hz, 2H),2.78-2.72 (m, 1H), 2.42-2.34 (m, 2H), 2.28 (s, 3H), 2.04-1.95 (m, 1H).MS (ESI) m/z 515.4 [M+H]⁺60: Synthesized according to general procedure A starting fromintermediate III (900 mg, 2.03 mmol) obtained in 57, wherein in step A.3the NH nucleophile is 1-methylpyrrolidin-3-ol (444 mg, 4.26 mmol);variant ii) was used in step A.4; and variant iii) was used in step A.5;and 13% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.63 (br s,1H), 9.51 (br s, 1H), 8.89 (s, l H), 8.61 (d, J=4.8 Hz, 1H), 8.36 (br s,1H), 7.90 (dt, J=1.7, 7.7 Hz, 1H), 7.64-7.55 (m, 2H), 7.42-7.30 (m, 2H),7.14 (s, 1H), 6.76 (dd, J=10.1, 17.0 Hz, 1H), 6.31 (dd, J=1.8, 17.1 Hz,1H), 5.84-5.78 (m, 1H), 5.33 (s, 2H), 5.10 (br s, 1H), 2.83 (br d, J=4.5Hz, 2H), 2.79-2.71 (m, 1H), 2.42-2.35 (m, 2H), 2.29 (s, 3H), 2.08-1.97(m, 1H). MS (ESI) m/z 549.3 [M+H]⁺, 571.3 [M+Na]⁺61: Synthesized according to general procedure A starting fromintermediate III (600 mg, 1.53 mmol) obtained in 58, wherein in step A.3the NH nucleophile is 1-methylpyrrolidin-3-ol (309 mg, 3.06 mmol);variant ii) was used in step A.4; and variant ii) was used in step A.5;and 7% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=10.05 (s,1H), 9.53 (s, 1H), 9.05 (s, 1H), 8.61 (br d, J=4.6 Hz, 1H), 8.53 (s,1H), 8.24-8.15 (m, 2H), 7.87 (t, J=7.6 Hz, 1H), 7.64-7.51 (m, 2H),7.43-7.33 (m, l H), 7.16 (s, l H), 6.75 (br dd, J=10.5, 16.9 Hz, 1H),6.32 (br d, J=17.2 Hz, 1H), 5.82 (br d, J=10.9 Hz, 1H), 5.29 (s, 2H),5.11 (br s, 1H), 2.83 (br d, J=3.9 Hz, 2H), 2.79-2.72 (m, 1H), 2.39-2.34(m, 2H), 2.29 (s, 3H), 2.05-1.95 (m, 1H). MS (ESI) m/z 498.4 [M+H]⁺62: Synthesized according to general procedure A starting fromintermediate III (820 mg, 1.93 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 3-(dimethylamino)cyclobutanol (444 mg, 3.85 mmol);variant i) was used in step A.4; and variant ii) was used in step A.5;and 12% overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.66 (s,1H), 9.60 (s, 1H), 8.90 (s, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.47 (s, 1H),7.97 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.68 (dd, J=2.5,9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.36 (dd, J=5.3, 7.0 Hz, 1H), 7.24(d, J=9.0 Hz, 1H), 7.09 (s, 1H), 6.75 (dd, J=10.2, 17.1 Hz, 1H), 6.32(dd, J=1.9, 16.9 Hz, 1H), 5.84-5.78 (m, 1H), 5.28 (s, 2H), 4.73 (quin,1=7.0 Hz, 1H), 2.78-2.68 (m, 2H), 2.40 (t, J=7.1 Hz, 1H), 2.07 (s, 6H),2.03-1.94 (m, 2H). MS (ESI) m/z 545.3[M+H]⁺, 567.3[M+Na]⁺63: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-phenoxyaniline (370 mg, 2.00 mmol); in step A.3 the OHnucleophile 2-morpholinoethanol (453 mg, 3.45 mmol); variant i) was usedin step A.4; and variant i) was used in step A.5; and 6% overall yieldfrom II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.71 (s, 1H), 9.58 (s, 1H), 8.86(s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.43-7.37(m, 2H), 7.31 (s, 1H), 7.13 (t, J=7.40 Hz, 1H), 7.04 (dd, J=11.8, 8.8Hz, 4H), 6.68 (dd, J=17.0, 10.0 Hz, 1H), 6.31 (dd, 1=17.0, 1.8 Hz, 1H),5.85-5.79 (m, 1H), 4.35 (t, J=5.8 Hz, 2H), 3.62-3.55 (m, 4H), 2.83 (t,J=5.6 Hz, 2H), 2.56-2.53 (m, 4H). MS (ESI) m/z 512.3 [M+H]⁺64: To a solution of intermediate III (800 mg, 1.88 mmol) obtained in 4and potassium carbonate (779 mg, 5.64 mmol, 3.00 eq) indimethylsulfoxide (10.0 mL) was added tert-butylN-pyrrolidin-3-ylcarbamate (700 mg, 3.76 mmol, 2.00 eq). The mixture wasstirred at 25° C. for 1 h. The residue was triturated with water (30.0mL) and filtered, the filter cake was dried under reduced pressure toafford tert-butyl(1-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)pyrrolidin-3-yl)carbamate(970 mg, 1.64 mmol, 87% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.90 (br s, 1H), 9.03 (s, 1H), 8.60 (br d, J=4.5 Hz, 1H),8.49 (s, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.88 (dt, J=1.5, 7.7 Hz, 1H), 7.71(br dd, J=2.0, 8.9 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 7.0Hz, 1H), 7.26 (br d, J=9.0 Hz, 2H), 7.00 (s, 1H), 5.29 (s, 2H), 4.11 (brs, 1H), 3.51-3.42 (m, 1H), 3.42-3.35 (m, 2H), 2.99 (br dd, J=4.5, 10.1Hz, 1H), 2.54 (s, 1H), 2.19-2.08 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s,9H).

A mixture of tert-butyl(1-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)pyrrolidin-3-yl)carbamate(770 mg, 1.30 mmol, 1.00 eq) in hydrochloric acid/ethyl acetate (10.0mL). The mixture was stirred at 25° C. for 2 h. The mixture wasconcentrated in vacuum. The residue was triturated with water (30.0 mL)and saturated sodium carbonate (5.00 mL). After filtration, the filtercake was dried in vacuum to afford7-(3-aminopyrrolidin-1-yl)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(570 mg, 1.16 mmol, 89% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.95 (br s, 1H), 9.01 (br s, 1H), 8.60 (br s, 1H), 8.42 (brs, 1H), 8.00 (br s, 1H), 7.87 (br d, J=6.8 Hz, 1H), 7.67 (br d, J=7.6Hz, 1H), 7.58 (br d, J=7.2 Hz, 1H), 7.36 (br s, 1H), 7.24 (br d, J=8.3Hz, 1H), 6.95 (br s, 1H), 5.28 (br s, 2H), 3.57-3.39 (m, 2H), 3.27-3.22(m, 1H), 2.83 (br s, 1H), 2.03 (br s, 1H), 1.98-1.63 (m, 2H).

To a solution of7-(3-aminopyrrolidin-1-yl)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(570 mg, 1.16 mmol, 1.00 eq) in acetonitrile (20.0 mL) was addedformaldehyde (940 mg, 11.6 mmol, 0.863 mL, 10.0 eq), sodium triacetoxyborohydride (786 mg, 3.71 mmol, 3.20 eq). The mixture was stirred at 25°C. for 12 h. The residue was triturated with water (30 mL) and filtered,the filter cake was dried under reduced pressure to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)pyrrolidin-1-yl)-6-nitroquinazolin-4-amine(500 mg, 0.962 mmol, 82% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.93 (br s, 1H), 9.04 (br s, 1H), 8.59 (br s, 1H), 8.48 (brs, 1H), 8.02 (br s, 1H), 7.88 (br s, 1H), 7.70 (br s, 1H), 7.59 (br s,1H), 7.37 (br s, 1H), 7.26 (br d, J=6.7 Hz, 1H), 7.04 (br s, 1H), 5.28(br s, 2H), 3.16 (br s, 4H), 2.77 (br s, 1H), 2.19 (br s, 6H), 2.14-2.02(m, 1H), 1.85 (br s, 1H). To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)pyrrolidin-1-yl)-6-nitroquinazolin-4-amine(500 mg, 0.962 mmol, 1.00 eq) and iron powder (376 mg, 6.73 mmol, 7.00eq) in methanol (25.0 mL) was added a solution of ammonium chloride (463mg, 8.65 mmol, 0.303 mL, 9.00 eq) in water (5.00 mL). The mixture wasstirred at 80° C. for 3 h.

The mixture was cooled to 25° C. and then concentrated in vacuum. Theresidue was triturated with methanol (100 mL) and filtered. The filtratewas concentrated to afford a residue. The residue was triturated withwater (30.0 mL) and saturated sodium carbonate (2.00 mL). Afterfiltration, the filter cake was washed with methanol (100 mL). Thefiltrate was concentrated in vacuum to affordNM-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)pyrrolidin-1-yl)quinazoline-4,6-diamine (570 mg, crude) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.24 (s, 1H), 8.59 (br d, J=4.6 Hz,1H), 8.34-8.28 (m, 1H), 8.09-7.99 (m, 1H), 7.90-7.85 (m, 1H), 7.71 (dd,J=2.1, 9.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.42-7.38 (m, 1H), 7.36 (br d,J=5.0 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 7.03 (s, 1H), 5.32-5.25 (m, 2H),5.09 (br s, 2H), 3.18 (br d, J=8.7 Hz, 4H), 2.41 (br s, 6H), 2.18-2.09(m, 1H), 2.04-1.87 (m, 1H), 1.35 (s, 1H).

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)pyrrolidin-1-yl)quinazoline-4,6-diamine (250 mg, 0.510 mmol, 1.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg,1.02 mmol, 2.00 eq) and pyridine (80.7 mg, 1.02 mmol, 0.0824 mL, 2.00eq) in N,N-dimethylformamide (3.00 mL) was added a solution of acrylicacid (0.500 M, 1.53 mL, 1.50 eq) in N,N-dimethylformamide. The mixturewas stirred at 20° C. for 1 h. The mixture was concentrated in vacuum.The residue was purified by prep-HPLC and lyophilized to afford 64(70.49 mg, 118 umol, 23% yield, 99%.o purity, formic acid) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.92 (br s, 1H), 9.50 (br s, 1H),8.62-8.57 (m, 1H), 8.42 (s, 1H), 8.23 (d, J=15.0 Hz, 1H), 8.20-8.19 (m,1H), 8.04 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.8, 7.7 Hz, 1H), 7.76-7.68 (m,1H), 7.58 (d, J=7.8 Hz, 1H), 7.39-7.34 (m, 1H), 7.26-7.20 (m, 1H), 6.86(s, 1H), 6.59-6.47 (m, 1H), 6.29 (dd, J=1.7, 17.1 Hz, 1H), 5.80 (dd,J=1.6, 10.3 Hz, 1H), 5.27 (s, 2H), 3.48-3.34 (m, 4H), 2.82-2.68 (m, 1H),2.19 (br s, 6H), 2.15-2.07 (m, 1H), 1.86-1.68 (m, 1H). MS (ESI) m/z544.4 [M+1]⁺

65: To a stirred suspension of 1-methylpiperazine (2.50 g, 25.0 mmol,1.00 eq), 3-chloro-3-methylbut-1-yne (3.07 g, 30.0 mmol, 1.20 eq),triethylamine (2.53 g, 25.0 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL)was added copper (I) chloride (336 mg, 3.39 mmol, 0.136 eq) at 0° C.under nitrogen. The mixture was purged by nitrogen for 0.1 h and stirredat 20° C. for 0.5 h. Water (80.0 mL) and 1 N aqueous hydrochloric acid(20.0 mL) were added and the mixture was concentrated under reducedpressure. The mixture was washed with ethyl acetate (2×20.0 mL) andbasified by addition of potassium carbonate (approx. 10.0 g). Themixture was extracted with ethyl acetate (3/20.0 mL), washed with brine(30.0 mL), drying with magnesium sulphate, and concentration to give1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (2.00 g, 12.0 mmol, 48%yield) as a brown solid. ¹H NMR (400 Hz, DMSO-d₆) δ=3.14 (s, 1H),2.57-2.51 (m, 2H), 2.31 (br s, 3H), 2.13 (s, 3H), 1.35-1.20 (m, 6H).

To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (0.400 g, 720 umol, 1.00 eq),1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (144 mg, 864 umol, 1.20eq), copper (I) iodide (27.4 mg, 144 umol, 0.200 eq) inN,N-dimethylformamide (5.00 mL) and triethylamine (2.00 mL) was addedtetrakis(triphenylphosphine)palladium (14.4 ug, 72.0 umol, 0.100 eq) at20° C. The mixture was stirred at 20° C. for 3 h. The mixture wasconcentrated in vacuum to give a residue. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/1 to ethylacetate/methanol/triethylamine=5/1/0.001) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-6-nitroquinazolin-4-amine(0.250 g, 437 umol, 60% yield) as a yellow solid.

MS (ESI) m/z 572.1 [M+H]⁺. ¹H NMR (400 Hz, DMSO-d₆) δ=9.46 (s, 1H), 8.72(s, 1H), 8.60 (br d, J=4.8 Hz, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.89 (brt, J=7.6 Hz, 1H), 7.72 (br d, J=7.6 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H),7.42-7.34 (m, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.31 (s, 2H), 3.40-3.36 (m,2H), 2.71 (br s, 3H), 2.26 (br s, 3H), 1.45 (s, 6H).

To a suspension ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-6-nitroquinazolin-4-amine (0.250 g, 437 umol, 1.00 eq),ammonium chloride (117 mg, 2.19 mmol, 5.00 eq) in methanol (10.0 mL) andwater (5.00 mL) was added iron powder (122 mg, 2.19 mmol, 5.00 eq) at20° C. The mixture was stirred at 80° C. for 1 h. The mixture wasfiltered, and the filtrate was concentrated in vacuum to give a residue.The residue was triturated with water (3.00 mL) to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)quinazoline-4,6-diamine (0.180 g, crude) as a yellow solid. MS (ESI) m/z542.3 [M+H]⁺

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)quinazoline-4,6-diamine(0.100 g, 185 umol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106mg, 553 umol, 3.00 eq), pyridine (0.500 M, 740 umol, 4.00 eq), acrylicacid (0.500 M, 222 umol, 1.20 eq) at 20° C. And the mixture was stirredat 20° C. for 12 h. The mixture was filtered. The filtrate was purifiedby prep-HPLC to give a crude product (30 mg), the crude product wasrepurified by prep-HPLC to give 65 (13.67 mg, 22.7 umol, 12% yield, 99%purity) as a yellow solid. ¹H NMR (400 Hz, DMSO-d₆) δ=9.87 (br s, 1H),9.82 (br s, 1H), 8.65 (s, 1H), 8.60 (br d, J=4.0 Hz, 1H), 8.57 (br s,1H), 8.03 (br s, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.79 (s, 1H), 7.72(br d, J=9.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 6.5 Hz,1H), 7.27 (d, J=8.8 Hz, 1H), 6.56 (br dd, J=9.7, 16.8 Hz, 1H), 6.32 (dd,J=1.8, 17.0 Hz, 1H), 5.87-5.79 (m, 1H), 5.29 (s, 2H), 2.65-2.60 (m, 4H),2.36-2.28 (m, 4H), 2.14 (s, 3H), 1.42 (s, 6H). MS (ESI) m/z 596.5,[M+H]⁺, 618.5 [M+Na]⁺

66: To a stirred suspension of 3-chloro-3-methylbut-1-yne (1.00 g, 9.75mmol, 1.10 mL, 1.00 eq), dimethylamine (1.03 g, 12.7 mmol, 1.16 mL, 1.30eq, HCl) and triethylamine (2.96 g, 29.2 mmol, 4.07 mL, 3.00 eq) intetrahydrofuran (15.0 mL) was added cuprous chloride (193 mg, 1.95 mmol,46.6 uL, 0.200 eq) under nitrogen atmosphere at 0° C. The mixture waspurged by nitrogen for 0.1 h, and stirred at 20° C. for 0.5 h. Themixture was added water (20.0 mL), hydrochloric acid (1.00 M, 10.0 mL)and concentrated under reduced pressure. After that the mixture waswashed with tert-butyl methyl ether (2×40.0 mL) and made basic byaddition of potassium carbonate (5.00 g). The residue was extracted withtert-butyl methyl ether (3×60.0 mL), washing with brine (30.0 mL), driedover magnesium sulphate, filtered and concentrated to giveN,N,2-trimethylbut-3-yn-2-amine (200 mg, 1.80 mmol, 18% yield) as lightbrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ=3.12 (s, 1H), 2.16 (s, 6H),1.28 (s, 6H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(4.00 g, 9.39 mmol, 1.00 eq) in dimethyl formamide (20.0 mL) was addedpotassium acetate (4.61 g, 47.0 mmol, 5.00 eq) at 15° C. The mixture wasstirred at 100° C. for 1 h. The mixture was concentrated to afford aresidue. The residue was diluted with water (50.0 mL). After filtration,the filter cake was washed with water (20.0 mL), dried in vacuum to give4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-ol(4.0 g, crude) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.07 (s,1H), 9.19 (br s, 1H), 8.68-8.52 (m, 2H), 8.00 (br s, 1H), 7.88 (br d,J=6.8 Hz, 1H), 7.69 (br d, J=7.6 Hz, 1H), 7.59 (br d, J=7.21 Hz, 1H),7.37 (br s, 1H), 7.28 (br d, 1=8.6 Hz, 1H), 7.20 (br s, 1H), 5.30 (s,2H).

To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-ol(4.00 g, 9.44 mmol, 1.00 eq) and pyridine (3.73 g, 47.2 mmol, 3.81 mL,5.00 eq) in dichloromethane (100 mL) was added trifluoromethanesulfonicanhydride (5.33 g, 18.9 mmol, 3.11 mL, 2.00 eq) at 0° C. The mixture wasstirred at 20° C. for 12 h. The mixture was concentrated to afford aresidue. The residue was purified by silica gel chromatography (silicagel column: 80 g; petroleum ether/ethyl acetate=1/1-0/1) to give4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (2.00 g, 3.60 mmol, 38% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.72 (s, 1H), 8.77 (s, 1H), 8.64-8.58(m, 1H), 8.04 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.92-7.87 (m, 1H), 7.70(dd, J=8.9, 2.6 Hz, 1H), 7.61-7.58 (m, 1H), 7.40-7.36 (m, 1H), 7.32 (d,J=9.0 Hz, 1H), 5.32 (s, 2H). MS (ESI) m/z 556.2 [M+H]⁺

To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (500 mg, 900 umol, 1.00 eq) in dimethylformamide (10.0 mL) was added N,N,2-trimethylbut-3-yn-2-amine (150 mg,1.35 mmol, 1.50 eq), copper iodide (85.7 mg, 450 umol, 0.500 eq),triethylamine (273 mg, 2.70 mmol, 376 uL, 3.00 eq),tetrakis(triphenylphosphine)palladium (104 mg, 90.0 umol, 0.100 eq) at20° C. The mixture was de-gassed with nitrogen and stirred at 20° C. for12 h under nitrogen. The mixture was concentrated under vacuum to givethe residue. The residue was purified by flash chromatography [silicagel column: 12 g; petroleum ether/ethyl acetate=10/1-0/1;dichloromethane/methanol=10/1] to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-6-nitroquinazolin-4-amine(460 mg, crude) as light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.40(br s, 1H), 9.47 (br s, 1H), 8.83 (br s, 1H), 8.73 (s, 1H), 8.61 (br d,J=4.8 Hz, 1H), 8.03 (br d, J=2.32 Hz, 2H), 7.89 (br d, J=1.6 Hz, 1H),7.76-7.71 (m, 1H), 7.58-7.53 (m, 2H), 5.32 (s, 2H), 2.52 (s, 6H), 1.53(s, 6H). MS (ESI) m/z 517.4 [M+H]⁺

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-6-nitroquinazolin-4-amine(400 mg, 774 umol, 1.00 eq) in methanol (20.0 mL)and water (4.00 mL) wasadded iron (216 mg, 3.87 mmol, 5.00 eq) and ammonium chloride (207 mg,3.87 mmol, 135 uL, 5.00 eq) at 20° C. The mixture was de-gassed withnitrogen and stirred at 70° C. for 1 h under nitrogen. The mixture wasfiltered to give the filtrate. The filtrate was purified byreverse-phase chromatographyN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)quinazoline-4,6-diamine(280 mg, 575 umol, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ=11.10 (br s,1H), 10.70 (br s, 1H), 8.74 (s, 1H), 8.62 (d, J=4.2 Hz, 1H), 7.95-7.89(m, 2H), 7.81 (s, 1H), 7.73 (s, 1H), 7.65-7.59 (m, 2H), 7.41 (dd, J=7.0,5.3 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 5.35 (s, 2H) 2.94 (s, 6H), 1.78 (s,6H).

To the solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)quinazoline-4,6-diamine(220 mg, 451.75 umol, 1 eq) and acrylic acid (65.1 mg, 904 umol, 62.0uL, 2.00 eq) in dimethyl formamide (5.00 mL) was added pyridine (71.5mg, 904 umol, 72.9 uL, 2.00 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 904umol, 2.00 eq) at 20° C. The mixture was stirred at 20° C. for 1 h. Themixture was filtered to give the filtrate. The filtrate was purified byprep-HPLC to give 66 (30.38 mg, 55.03 umol, 12.18% yield, 98% purity) asyellow solid. ¹H NMR (400 MHz, CD₃OD) δ=8.66 (s, 1H), 8.58 (d, J=4.52Hz, 1H), 8.53 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.94-7.90 (m, 1H), 7.89(s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.63 (dd, J=8.86, 2.63 Hz, 1H), 7.41(dd, J=6.9, 5.32 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.63-6.53 (m, 1H),6.53-6.45 (m, 1H), 5.92 (dd, J=9.8, 2.0 Hz, 1H), 5.30 (s, 2H), 2.44 (s,6H), 1.56 (s, 6H). MS (ESI) m/z 541.4 [M+H]⁺

67: Synthesized according to general procedure A starting fromintermediate III (800 mg, 1.88 mmol) obtained in 4, wherein in step A.3the OH nucleophile is 1-methylpyrrolidin-3-ol (380 mg, 3.76 mmol);variant ii) was used in step A.4; and 24% overall yield from III. ¹H NMR(400 MHz, DMSO-d₆) δ=10.14 (br s, 1H), 9.68 (br s, 1H), 8.69 (br s, 1H),8.60 (dd, J=0.7, 4.8 Hz, 1H), 8.48 (s, 1H), 8.22 (s, 2H), 8.01-7.95 (m,1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.67 (dd, J=2.3, 9.0 Hz, 1H), 7.58(d, J=7.8 Hz, 1H), 7.37 (dd, J=4.9, 6.6 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H),7.18 (s, 1H), 5.28 (s, 2H), 5.16 (br s, 1H), 3.03-2.79 (m, 3H),2.57-2.51 (m, 1H), 2.42-2.37 (m, 4H), 2.07 (br s, 3H), 2.00-1.94 (m,1H). MS (ESI) m/z 543.4 [M+H]⁺68: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-methyl-4-((6-methylpyridin-3-yl)oxy)aniline (500 mg, 2.33mmol); in step A.3 the OH nucleophile 1-methylpyrrolidin-3-ol (414 mg,4.09 mmol): variant ii) was used in step A.4; and variant i) was used instep A.5; and 27% overall yield from II. ¹H NMR (400 MHz, DMSO-d₆)δ=9.75-9.54 (m, 2H), 8.94 (br s, 1H), 8.48 (s, 1H), 8.23 (br d, J=4.8Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.67 (dd,J=2.6, 8.7 Hz, 1H), 7.26-7.22 (m, 1H), 7.22-7.18 (m, 1H), 7.17 (br s,1H), 6.94 (d, J=8.7 Hz, 1H), 6.82-6.70 (m, 1H), 6.32 (br d, 0.1=17.0 Hz,1H), 5.86-5.79 (m, 1H), 5.16 (br s, 1H), 3.05-2.82 (m, 3H), 2.52 (br d,J=1.8 Hz, 1H), 2.44 (s, 3H), 2.42-2.36 (m, 3H), 2.35-2.30 (m, 1H), 2.20(s, 3H), 2.03 (br d, J=4.0 Hz, 1H). MS (ESI) m/z 511.4 [M+H]⁺69: Synthesized according to general procedure A starting fromintermediate III (400 mg, 939 umol) obtained in 4, wherein in step A.3the OH nucleophile is 3-(4-methylpiperazin-1-yl)propan-1-ol (193 mg,1.22 mmol); variant ii) was used in step A.4; and variant ii) was usedin step A.5; and 64% overall yield from III. ¹H NMR (400 MHz, CDCl₃)δ=9.10 (s, 1H), 8.64 (s, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.89(d, J=2.6 Hz, 1H), 7.81-7.73 (m, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.63 (s,1H), 7.51 (dd, J=8.8, 2.6 Hz, 1H), 7.54 (br s, 1H), 7.28-7.23 (m, 2H),7.01 (d, J=8.8 Hz, 1H), 6.55-6.45 (m, 1H), 6.42-6.30 (m, 1H), 5.88 (dd,J=10.2, 1.0 Hz, 1H), 5.31 (s, 2H), 4.30 (t, J=6.4 Hz, 2H), 2.66-2.55 (m,4H), 2.51 (br s, 4H), 2.32 (s, 3H), 2.19-2.09 (m, 4H). MS (ESI) m/z588.4 [M+H]⁺70: Synthesized according to general procedure C starting fromintermediate XV (600 mg, 1.15 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 1-methylpiperazine (412 mg, 4.11 mmol); variant ii) was usedin step C.5; and 17% overall yield from XV. ¹H NMR (400 MHz, CDCl₃)δ=8.90 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 7.88(d, J=2.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.69-7.64 (m, 1H), 7.51-7.44 (m,2H), 7.26-7.22 (m, 1H), 7.02 (d, J=9.2 Hz, 1H), 5.31 (s, 2H), 4.36 (t,J=5.6 Hz, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.75-2.39 (m, 8H), 2.32 (s, 3H),2.08 (s, 3H). MS (ESI) m/z 586.3 [M+H]⁺71: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 6-(2-pyridylmethoxy)pyridin-3-amine (961 mg); in step A.3the OH nucleophile is 2-morpholinoethanol (304 mg, 2.32 mmol); varianti) was used in step A.4; and variant i) was used in step A.5; and 7%overall yield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.14 (s, 1H), 8.67-8.58(m, 2H), 8.45 (s, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.8, 8.8 Hz,1H), 7.71 (dt, J=1.6, 7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.37 (s, 1H),7.29 (s, 1H), 7.26-7.20 (m, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.53-6.45 (m,1H), 6.43-6.32 (m, 1H), 5.88 (dd, J=1.2, 10.0 Hz, 1H), 5.55 (s, 2H),4.37 (t, J=5.6 Hz, 2H), 3.80-3.71 (m, 4H), 2.92 (t, J=5.6 Hz, 2H),2.64-2.55 (m, 4H). MS (ESI) m/z 528.4 [M+H]⁺72: Synthesized according to general procedure A starting fromintermediate III (400 mg, 939 umol) obtained in 71, wherein in step A.3the OH nucleophile is (3R)-1-methylpyrrolidin-3-ol (247 mg, 2.45 mmol);variant ii) was used in step A.4; and variant ii) was used in step A.5;and 5% overall yield from I. ¹H NMR (400 MHz, CDCl₃) δ=9.15 (s, 1H),8.99 (br s, 1H), 8.63 (d, J=4.4 Hz, 1H), 8.59 (s, 1H), 8.39 (d, J=2.4Hz, 1H), 8.03 (dd, J=2.8, 8.8 Hz, 1H), 7.74-7.67 (m, 2H), 7.49 (d, J=8.0Hz, 1H), 7.25-7.20 (m, 1H), 7.15 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.61(br s, 1H), 6.53-6.46 (m, 1H), 5.86-5.80 (m, 1H), 5.54 (s, 2H),5.17-5.08 (m, 1H), 3.49-3.17 (m, 2H), 2.87-2.73 (m, 1H), 2.65-2.50 (m,5H), 2.30-2.20 (m, 1H). MS (ESI) m/z 498.4[M+H]⁺73: Synthesized according to general procedure A starting fromintermediate III (700 mg, 1.73 mmol) obtained in 68, wherein in step A.3the OH nucleophile is 2-morpholinoethanol (453 mg, 3.45 mmol); variantii) was used in step A.4; and variant i) was used in step A.5; and 39%overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (br s, 1H),9.59 (s, 1H), 8.86 (s, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 8.18 (d, J=2.7Hz, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.67 (dd, J=2.4, 8.7 Hz, 1H), 7.31 (s,1H), 7.26-7.22 (m, 1H), 7.22-7.18 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.68(dd, J=10.3, 17.0 Hz, 1H), 6.31 (dd, J=1.9, 17.1 Hz, 1H), 5.85-5.79 (m,1H), 4.34 (t, J=5.7 Hz, 2H), 3.59-3.55 (m, 4H), 2.82 (t, J=5.7 Hz, 2H),2.55-2.51 (m, 4H), 2.51-2.48 (m, 1H), 2.44 (s, 3H), 2.20 (s, 3H). MS(ESI) m/z 541.2 [M+H]⁺74: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-(4-chlorophenoxy)aniline (579 mg, 2.64 mmol); in step A.3the OH nucleophile is 2-morpholinoethanol (166 mg, 1.27 mmol); variantii) was used in step A.4; and variant ii) was used in step A.5; and 17%overall yield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.24 (s, 1H), 8.97 (s,1H), 8.64 (s, 1H), 8.34 (s, 1H), 7.70 (d, J=9.0 Hz, 2H), 7.51 (s, 1H),7.35-7.30 (m, 2H), 7.07 (d, J=9.0 Hz, 2H), 7.03-6.99 (m, 2H) 6.66-6.58(m, 1H), 6.55-6.50 (m, 1H), 5.90 (dd, J=9.8, 1.6 Hz, 1H), 4.42 (t, J=5.4Hz, 2H), 3.89-3.81 (m, 4H), 3.12 (t, J=5.4 Hz, 2H), 2.83 (br d, J=4.2Hz, 4H). MS (ESI) m/z 546.3 [M+H]⁺75: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-(pyridin-3-yloxy)aniline (409 mg, 2.20 mmol); in step A.3the OH nucleophile is 2-morpholinoethanol (939 mg, 7.16 mmol); variantii) was used in step A.4; and variant i) was used in step A.5; and 4%overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.75 (s, 1H), 9.61(s, 1H), 8.87 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.36 (t, J=2.8 Hz,1H), 7.85 (d, J=8.8 Hz, 2H), 7.44 (br s, 2H), 7.32 (s, 1H), 7.12 (d,J=8.7 Hz, 2H), 6.69 (br dd, J=10.6, 16.7 Hz, 1H), 6.31 (d, J=16.9 Hz,1H), 5.83 (d, J=10.6 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 3.58 (t, J=4.4 Hz,4H), 2.83 (t, J=5.6 Hz, 2H), 2.56-2.52 (m, 4H). MS (ESI) m/z 513.4[M+H]⁺76: Synthesized according to general procedure C starting fromintermediate XV (2.00 g, 6.94 mmol) obtained in 28, wherein in step C₁₋₄HNR′R″ is N,N-dimethylpiperidin-4-amine (609 mg, 3.70 mmol, HCl);variant ii) was used in step C.5; variant i) was used in step C₁₋₆; and6% overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s, 1H), 9.59(s, 1H), 8.85 (s, 1H), 8.61 (d, J=4.6 Hz, 1H), 8.49 (s, 1H), 8.00 (d,J=2.6 Hz, 1H), 7.89 (dt, J=1.7, 7.6 Hz, 1H), 7.70 (dd, J=2.6, 8.9 Hz,1H), 7.60 (d, J=7.9 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (s, 1H), 7.26 (d,J=9.2 Hz, 1H), 6.69 (dd, J=10.2, 17.2 Hz, 1H), 6.32 (dd, J=1.8, 17.1 Hz,1H), 5.91-5.74 (m, 1H), 5.29 (s, 2H), 4.32 (t, 1=5.7 Hz, 2H), 2.99 (brd, J=11.7 Hz, 2H), 2.80 (t, J=5.7 Hz, 2H), 2.15 (s, 6H), 2.10-1.96 (m,3H), 1.69 (br d, J=11.9 Hz, 2H), 1.43-1.30 (m, 2H). MS (ESI) m/z 602.5[M+H]⁺77: Synthesized according to general procedure C starting fromintermediate XV (100 mg, 206 umol) obtained in 28, wherein in step C₁₋₄HNR′R″ is 2-methyloctahydropyrrolo[3,4-c]pyrrole (66.9 mg, 411 umol,HCl); variant ii) was used in step C.5; variant i) was used in stepC₁₋₆; and 10% overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68(s, 1H), 9.60 (s, 1H), 8.85 (s, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.50 (s,1H), 8.00 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd,J=2.5, 9.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.41-7.34 (m, 1H), 7.30 (s,1H), 7.26 (d, J=9.0 Hz, 1H), 6.68 (dd, J=10.1, 17.1 Hz, 1H), 6.31 (dd,J=1.7, 17.1 Hz, 1H), 5.88-5.75 (m, 1H), 5.29 (s, 2H), 4.32 (br t, 1=5.6Hz, 2H), 2.86 (br t, J=5.6 Hz, 2H), 2.80-2.71 (m, 2H), 2.57 (br s, 2H),2.43-2.35 (m, 2H), 2.31 (br dd, J=4.1, 8.7 Hz, 2H), 2.24 (dd, J=2.8, 8.8Hz, 2H), 2.17 (s, 3H). MS (ESI) m/z 600.1 [M+H]⁺78: Synthesized according to general procedure A starting fromintermediate III (400 mg, 939 umol) obtained in 4, wherein in step A.3the NH nucleophile is N,N-dimethylpiperidin-4-amine (168 mg, 1.32 mmol);variant ii) was used in step A.4; variant i) was used in step A.5; and45% overall yield from III. ¹H NMR (400 MHz, CDCl₃) δ=9.00 (s, 1H), 8.73(s, 1H), 8.61 (br s, 1H), 8.60 (s, 1H), 8.45 (br s, 1H), 7.88 (d, J=2.6Hz, 1H), 7.80-7.76 (m, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.54 (d, J=2.6 Hz,1H), 7.52 (s, 1H), 7.28-7.23 (m, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.54-6.48(m, 2H), 5.88 (dd, J=7.0, 4.4 Hz, 1H), 5.29 (s, 2H), 3.28 (br d, J=12.0Hz, 2H), 2.89-2.82 (m, 1H), 2.77 (br t, 0.1=11.6 Hz, 2H), 2.70 (s, 6H),2.28-2.09 (m, 4H). MS (ESI) m/z 558.4 [M+H]⁺79: The reaction mixture of 4-chloro-7-fluoro-6-nitroquinazoline (800mg, 3.52 mmol, 1.00 eq) and 4-(pyridin-2-ylmethoxy)aniline (704 mg, 3.52mmol, 1.00 eq) in acetonitrile (20.0 mL) was stirred for 2 h at 25° C.The mixture was concentrated under vacuum to give7-fluoro-6-nitro-N-(4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine(1.5 g, crude) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.69 (br s,1H), 9.93 (d, J=7.70 Hz, 1H), 8.92 (s, 1H), 8.83 (br d, J=4.77 Hz, 1H),8.29-8.22 (m, 1H), 8.04 (d, J=11.86 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H),7.78 (d, J=8.93 Hz, 2H), 7.75-7.70 (m, 1H), 7.26 (d, J=9.05 Hz, 2H),5.47 (s, 2H).

A mixture of7-fluoro-6-nitro-N-(4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine(400 mg, 1.02 mmol, 1.00 eq), tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate (444 mg, 2.04 mmol, 2.00 eq)and potassium tert-butoxide (344.07 mg, 3.07 mmol, 3.00 eq) indimethylsulfoxide (10.0 mL) was stirred for 1 h at 20° C. The mixturewas filtered to give the filtrate. The filtrate was purified byreverse-phase chromatography [column: 80 g, CH₃CN/H₂O (FA:0.1%)=0/1-1/1] to give tert-butyl3-(((6-nitro-4-((4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(340 mg, 578 umol, 57% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.06 (s, 1H), 9.24 (s, 1H), 8.66-8.57 (m,2H), 7.86 (br t, J=7.58 Hz, 1H), 7.69 (br d, J=8.93 Hz, 2H), 7.61 (s,1H), 7.55 (br d, J=7.95 Hz, 1H), 7.41-7.34 (m, 1H), 7.13-7.07 (m, 2H),5.21 (s, 2H), 4.59 (br t, J=8.74 Hz, 1H), 4.48 (br d, J=13.57 Hz, 1H),4.28 (br s, 1H), 3.97 (br d, J=11.37 Hz, 1H), 3.83 (br d, J=8.80 Hz,1H), 3.72 (br s, 1H), 3.55 (br d, J=9.17 Hz, 1H), 3.47-3.41 (m, 2H),1.35 (br s, 9H).

The mixture of tert-butyl3-(((6-nitro-4-((4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(0.450 g, 764.51 umol, 1.00 eq), iron (213 mg, 3.82 mmol, 5.00 eq), andammonium chloride (204 mg, 3.82 mmol, 134 uL, 5.00 eq) in methanol (10.0mL) and water (2.00 mL) was stirred for 1 h at 70° C. The mixture wasfiltered to give the filtrate. The filtrate was purified byreverse-phase chromatography to give tert-butyl3-(((6-amino-4-((4-(pyridin-2-ylmethoxy)phenyl)-amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(200 mg, 358 umol, 47% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=10.07 (br s, 1H), 8.60 (d, J=4.16 Hz, 1H), 8.48 (s, 1H), 7.86(td, 1=7.70, 1.71 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (d, J=7.82 Hz, 1H),7.49 (s, 1H), 7.37 (dd, J=7.09, 5.14 Hz, 1H), 7.17 (br s, 1H), 7.08 (d,J=9.05 Hz, 2H), 5.62 (br s, 2H), 5.21 (s, 2H), 4.47-4.31 (m, 3H), 4.05(br d, J=11.86 Hz, 1H), 3.84 (br d, J=8.68 Hz, 1H), 3.68 (br s, 1H),3.57 (br d, J=11.74 Hz, 1H), 3.46-3.41 (m, 2H), 1.42 (br s, 9H).

To a solution of tert-butyl3-(((6-amino-4-((4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(200 mg, 358 umol, 1.00 eq) and acrylic acid (38.7 mg, 537 umol, 36.9uL, 1.50 eq) in dimethyl formamid (5.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 716umol, 2.00 eq) and pyridine (56.6 mg, 716 umol, 57.8 uL, 2.00 eq) at 25°C. The reaction mixture was stirred for 1 h at 25° C. Acrylic acid (51.6mg, 716 umol, 49.1 uL, 2.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 716umol, 2.00 eq) and pyridine (56.6 mg, 716 umol, 57.8 uL, 2.00 eq) wereadded to the mixture. The resulting mixture was stirred for 6 h at 25°C. The mixture was filtered to give the filtrate. The filtrate waspurified by prep-HPLC to give tert-butyl3-(((6-acrylamido-4-((4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(50.0 mg, 81.6 umol, 23% yield) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ=9.64 (s, 1H), 8.96 (br s, 1H), 8.60 (br d, J=4.04 Hz,1H), 8.43 (s, 1H), 7.86 (br t, J=7.40 Hz, 1H), 7.65 (br d, J=8.68 Hz,2H), 7.55 (d, J=7.58 Hz, 1H), 7.40-7.34 (m, 2H), 7.05 (br d, J=9.05 Hz,2H), 6.71 (br dd, J=16.81, 10.33 Hz, 1H), 6.33 (br d, J=16.02 Hz, 1H),5.84 (br d, J=10.51 Hz, 1H), 5.20 (s, 2H), 4.48 (br s, 1H), 4.33 (br s,2H), 4.08 (br d, J=11.74 Hz, 1H), 3.85 (br d, J=10.15 Hz, 1H), 3.69 (brd, J=11.86 Hz, 1H), 3.54 (br d, J=10.88 Hz, 1H), 3.46-3.38 (m, 2H), 1.40(br s, 9H).

The reaction mixture of tert-butyl3-(((6-acrylamido-4-((4-(pyridin-2-ylmethoxy)phenyl)-amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(45.0 mg, 73.5 umol, 1.00 eq) and trifluoroacetic acid (3.08 g, 27.0mmol, 2.00 mL, 368 eq) in dichloromethane (10.0 mL) was stirred for 2 hat 0° C. The mixture was concentrated under vacuum to give the crudeproduct. The crude product was purified by prep-HPLC to give 79 (30 mg,58.53 umol, 79.69% yield, 100% purity) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ=9.67 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.60 (d,J=4.03 Hz, 1H), 8.43 (s, 1H), 7.86 (td, J=7.70, 1.83 Hz, 1H), 7.69-7.63(m, 2H), 7.55 (d, 1=7.82 Hz, 1H), 7.36 (dd, J=6.97, 5.38 Hz, 1H), 7.24(s, 1H), 7.08-7.02 (m, 2H), 6.71 (dd, J=16.93, 10.33 Hz, 1H), 6.33 (dd,J=17.00, 1.96 Hz, 1H), 5.88-5.82 (m, 1H), 5.20 (s, 2H), 4.15-4.10 (m,1H), 4.07-4.01 (m, 1H), 3.88 (dd, J=10.70, 2.75 Hz, 1H), 3.70 (br d,J=10.76 Hz, 1H), 3.46-3.39 (m, 1H), 3.29-3.26 (m, 2H), 3.18 (br s, 1H),2.89-2.76 (m, 2H). MS (ESI) m/z 513.5 [M+H]⁺

80: Synthesized according to general procedure C, wherein in step C.1the ethane-1,2-diol (22.2 g, 358 mmol); in step C₁₋₃ H₂N—X is4-(pyridin-2-ylmethoxy)aniline (1.39 g, 6.94 mmol); in step C₁₋₄ HNR′R″is N,N-dimethylpiperidin-4-amine (454 mg, 3.54 mmol); variant ii) wasused in step C.5; and variant i) was used in step C₁₋₆; and 31% overallyield from 1. ¹H NMR (400 MHz, DMSO-d₆) δ=9.62 (br d, J=3.6 Hz, 2H),8.84 (s, 1H), 8.60 (br d, J=3.8 Hz, 1H), 8.42 (s, 1H), 7.85 (br t, J=6.8Hz, 1H), 7.66 (br d, J=8.8 Hz, 2H), 7.55 (br d, J=7.4 Hz, 1H), 7.40-7.33(m, 1H), 7.28 (s, 1H), 7.05 (br d, J=9.0 Hz, 2H), 6.68 (br dd, J=17.0,10.0 Hz, 1H), 6.31 (br d, J=17.2 Hz, 1H), 5.81 (br d, J=10.0 Hz, 1H),5.20 (s, 2H), 4.31 (br s, 2H), 2.98 (br d, J=11.4 Hz, 2H), 2.79 (br s,2H), 2.14 (s, 6H), 2.09 (br d, J=4.8 Hz, 2H), 2.02 (br d, J=8.6 Hz, 1H),1.68 (br d, J=11.2 Hz, 2H), 1.45-1.30 (m, 2H). MS (ESI) m/z 568.6 [M+H]⁺81: Synthesized according to general procedure C starting fromintermediate XV (800 mg, 1.77 mmol) obtained in 80, wherein in step C₁₋₄HNR′R″ is 2-methyloctahydropyrrolo[3,4-c]pyrrole (881 mg, 4.43 mmol,2HCl); variant ii) was used in step C.5; variant i) was used in stepC₁₋₆; and 8% overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.74 (s,1H), 9.70-9.55 (m, 1H), 8.85 (s, 1H), 8.60 (br d, J=4.8 Hz, 1H), 8.43(s, 1H), 8.28 (s, 3H), 7.85 (td, 1=7.6, 1.6 Hz, 1H), 7.66 (br d, J=9.0Hz, 2H), 7.55 (br d, J=7.8 Hz, 1H), 7.36 (dd, J=7.0, 5.0 Hz, 1H), 7.29(s, 1H), 7.05 (br d, J=9.0 Hz, 2H), 6.72 (br dd, J=17.0, 10.2 Hz, 1H),6.32 (br dd, J=17.0, 1.6 Hz, 1H), 5.87-5.76 (m, 1H), 5.20 (s, 2H), 4.35(br t, J=5.2 Hz, 2H), 2.98 (br t, J=5.2 Hz, 2H), 2.90-2.82 (m, 2H),2.77-2.67 (m, 4H), 2.63-2.54 (m, 4H), 2.44 (s, 3H). MS (ESI) m/z 566.6[M+H]⁺.82: A mixture of 4-chloro-7-fluoro-6-nitro-quinazoline (2.10 g, 9.24mmol, 1.10 eq) and 3-methyl-4-((6-methylpyridin-3-yl)oxy)aniline (1.80g, 8.40 mmol, 1.00 eq) in propan-2-ol (30.0 mL) was stirred at 90° C.for 2 h. The mixture was cooled to 25° C. and concentrated in vacuum.The residue was triturated with ethyl acetate (20.0 mL) and filtered,the filter cake was dried under reduced pressure to afford7-fluoro-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(3.70 g, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.29 (brs, 1H), 9.83 (d, J=7.8 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J=2.8 Hz, 1H),7.92 (d, J=12.1 Hz, 1H), 7.88 (dd, J=2.8, 8.7 Hz, 1H), 7.80 (d, J=2.2Hz, 1H), 7.76-7.70 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 2.65 (s, 3H), 2.25(s, 3H).

To a solution of7-fluoro-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(3.70 g, 9.13 mmol, 1.00 eq) in N,N-dimethylformamide (40.0 mL) wasadded potassium acetate (4.48 g, 45.6 mmol, 5.00 eq). The mixture wasstirred at 100° C. for 2 h. The mixture was concentrated in vacuum. Themixture was partitioned between ethyl acetate (100 mL) and water (30.0mL). The aqueous phase was extracted with ethyl acetate (2-100 mL). Thecombined organic phase was washed with brine (2×30.0 mL), dried withanhydrous sodium sulfate, filtered and concentrated in vacuum to afford4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-ol(2.40 g, 5.95 mmol, 65% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d₆) δ=9.97 (br s, 1H), 9.15 (s, 1H), 8.46 (s, 1H), 8.24-8.14 (m,1H), 7.74 (s, 1H), 7.68 (br d, J=8.8 Hz, 1H), 7.25-7.23 (m, 1H),7.22-7.19 (m, 1H), 7.08 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 2.44 (s, 3H),2.21 (s, 3H).

To a solution of4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-ol(1.90 g, 4.71 mmol, 1.00 eq) and pyridine (1.86 g, 23.6 mmol, 1.90 mL,5.00 eq) in dichloromethane (30.0 mL) was added trifluoromethanesulfonicanhydride (2.66 g, 9.42 mmol, 1.55 mL, 2.00 eq) at 0° C. The mixture wasstirred at 25° C. for 2 h. The mixture was concentrated in vacuum. Theresidue was purified by silica gel chromatography to afford4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (700 mg, 1.31 mmol, 27% yield) as a yellowsolid. 1H NMR (400 MHz, DMSO-d₆) δ=10.61 (s, 1H), 9.76 (s, 1H), 9.15 (s,1H), 8.51 (s, 1H), 8.24-8.17 (m, 2H), 8.04 (s, 1H), 7.69-7.63 (m, 1H),6.99 (d, J=8.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 2.45 (s, 3H), 1.98 (s,3H).

To a solution of4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (600 mg, 1.12 mmol, 1.00 eq) inN,N-dimethylformamide (10.0 mL) was addedN,N,2-trimethylbut-3-yn-2-amine (187 mg, 1.68 mmol, 1.50 eq), copper (I)iodide (107 mg, 0.560 mmol, 0.500 eq), triethylamine (340 mg, 3.36 mmol,0.468 mL, 3.00 eq), tetrakis[triphenylphosphine]palladium(0) (129 mg,0.112 mmol, 0.100 eq) at 25° C. The mixture was stirred at 25° C. for 12h. The mixture was concentrated in vacuum. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/0 to 0/1) toafford7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(360 mg, 0.725 mmol, 64% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d₆) δ=10.35 (s, 1H), 9.47 (s, 1H), 8.77-8.63 (m, 1H), 8.19 (s, 1H),7.96 (s, 1H), 7.77 (br d, J=2.1 Hz, 1H), 7.69 (dd, J=2.4, 8.9 Hz, 1H),7.27-7.23 (m, 2H), 6.97 (d, J=8.8 Hz, 1H), 2.44 (s, 3H), 2.35 (br s,6H), 2.23 (s, 3H), 1.46 (s, 6H).

To a solution of7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(310 mg, 0.624 mmol, 1.00 eq) and iron powder (244 mg, 4.37 mmol, 7.00eq) in methanol (15.0 mL) was added a solution of ammonium chloride (301mg, 5.62 mmol, 0.196 mL, 9.00 eq) in water (3.00 mL). The mixture wasstirred at 80° C. for 2 h. The residue was added methanol (100 mL) andstirred at 55° C. for 0.5 h. After filtration, the filtrate wasconcentrated to afford a residue. The residue was triturated with water(30.0 mL) and saturated sodium carbonate (2.00 mL). After filtration,the filter cake was washed with methanol (100 mL). The filtrate wasconcentrated in vacuum to afford7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-N4-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)quinazoline-4,6-diamine(230 mg, 0.493 mmol, 78% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d₆) δ=9.47 (s, 1H), 8.33 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J=2.4Hz, 1H), 7.75 (d, J=4.5 Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.68 (d,J=2.4 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 5.47 (s, 2H), 2.43 (s, 3H),2.29 (s, 6H), 2.19 (s, 3H), 1.46 (s, 6H).

To a solution of7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-N4-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)quinazoline-4,6-diamine(210 mg, 0.450 mmol, 1.00 eq), pyridine (178 mg, 2.25 mmol, 0.182 mL,5.00 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(431 mg, 2.25 mmol, 5.00 eq) in N,N-dimethylformamide (3.00 mL) wasadded a solution of acrylic acid (0.500 M, 3.60 mL, 4.00 eq) inN,N-dimethylformamide. The mixture was stirred at 25° C. for 2 h. Themixture was quenched by methanol (2.00 mL) and concentrated in vacuum.The residue was purified by prep-HPLC and lyophilized to affordN-(7-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)acrylamide(82) (24.35 mg, 46.3 umol, 10% yield, 99% purity) as yellow solid. 1HNMR (400 MHz, DMSO-d₆) δ=9.87 (d, J=4.5 Hz, 2H), 8.69 (s, 1H), 8.58 (s,1H), 8.19 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.71(dd, J=2.6, 8.7 Hz, 1H), 7.28-7.22 (m, 2H), 6.97 (d, J=8.8 Hz, 1H),6.60-6.51 (m, 1H), 6.33 (dd, J=1.8, 17.1 Hz, 1H), 5.84 (dd, J=1.8, 10.2Hz, 1H), 2.45 (s, 3H), 2.26 (s, 6H), 2.22 (s, 3H), 1.42 (s, 6H). MS(ESI) m/z 521.5 [M+1]+

83: To a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (1.16 g,6.02 mmol, 1.20 eq) and potassium carbonate (1.39 g, 10.0 mmol, 2.00 eq)in methanol (20.0 mL) was added tert-butyl 2-formylpyrrolidine-1-carboxylate (1.00 g, 5.02 mmol, 1.00 eq) at 20° C. The mixture wasstirred at 20° C. for 12 h. The mixture was concentrated to dryness anddiluted with ethyl acetate (20.0 mL). After filtration, the filtrate wasconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=5/1) to give tert-butyl2-ethynylpyrrolidine-1-carboxylate (800 mg, 4.10 mmol, 81% yield) as awhite solid. ¹H NMR (400 MHz, Chloroform-d) δ=4.56-4.29 (m, 1H), 3.46(br d, J=9.40 Hz, 1H), 3.30 (br s, 1H), 2.34-2.14 (m, 1H), 2.12-1.96 (m,3H), 1.89 (br s, 1H), 1.47 (s, 9H).

To a solution of tert-butyl 2-ethynylpyrrolidine-1-carboxylate (386 mg,1.98 mmol, 1.10 eq),4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethane-sulfonate(1.00 g, 1.80 mmol, 1.00 eq), copper iodide (68.5 mg, 360 umol, 0.200eq) and triethylamine (12.1 g, 120 mmol, 16.7 mL, 66.6 eq) indimethylformamide (10.0 mL) was addedtetrakis[triphenylphosphine]palladium(0) (208 mg, 180 umol, 0.100 eq) at15° C. The mixture was stirred at 15° C. for 12 h. The reaction wasconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/1-0/1) to givetert-butyl2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (1.00 g, 1.66 mmol, 92% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.4 (s, 1H), 9.4 (s, 1H), 8.7(s, 1H), 8.6 (br d, J=4.28 Hz, 1H), 8.0 (d, J=2.57 Hz, 1H), 8.0 (s, 1H),7.9 (s, 1H), 7.9 (td, J=7.70, 1.83 Hz, 1H), 7.7 (dd, J=9.05, 2.57 Hz,1H), 7.4 (dd, J=6.60, 4.89 Hz, 1H), 7.3 (d, J=9.05 Hz, 1H), 5.3 (s, 2H),4.7 (br s, 1H), 3.4-3.5 (m, 2H), 2.2 (br s, 1H), 2.0-2.1 (m, 2H), 1.9(br s, 1H), 1.4 (s, 9H).

To a solution of tert-butyl2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (400 mg, 666 umol, 1.00 eq) andammonium chloride (400 mg, 7.48 mmol, 262 uL, 11.3 eq) in methanol (13.0mL) and water (13.0 mL) was added iron (325 mg, 5.82 mmol, 8.75 eq) at20° C. The mixture was heated to 80° C. and stirred at 80° C. for 1 h.The combined mixture was concentrated to afford a residue. The residuewas diluted with water (10.0 mL), saturated sodium carbonate (5.00 mL)and the mixture was stirred for 30 min. After filtration, the filtratewas extracted with ethyl acetate (2×30.0 mL) to recover the product. Thecombined organic layer were concentrated to afford crude product to givetert-butyl2-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(300 mg, crude) as a brown oil. 1H NMR (400 MHz, DMSO-d₆) δ=9.5 (s, 1H),8.6-8.6 (m, 1H), 8.3 (s, 1H), 8.0 (d, J=2.57 Hz, 1H), 7.9 (td, J=7.70,1.71 Hz, 1H), 7.7 (dd, J=9.05, 2.57 Hz, 1H), 7.5-7.7 (m, 2H), 7.5 (br s,1H), 7.4 (dd, J=6.97, 5.38 Hz, 1H), 7.2 (d, J=9.05 Hz, 1H), 5.3 (s, 2H),4.7 (dd, J=7.64, 3.36 Hz, 1H), 3.4-3.5 (m, 2H), 2.2 (br d, J=7.46 Hz,1H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 1H), 1.8-1.9 (m, 1H), 1.5 (s, 7H),1.4-1.5 (m, 1H).

To a solution of tert-butyl2-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (270 mg, 473 umol, 1.00 eq) andpyridine (748 mg, 9.46 mmol, 20.0 eq) in dioxane (5.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (906 mg,4.73 mmol, 10.0 eq) and acrylic acid (341 mg, 4.73 mmol, 10.0 eq) at 0°C. The mixture was stirred at 15° C. for 5 h. The mixture was filteredto afford a solution. The solution was purified by prep-HPLC andlyophilized to give tert-butyl2-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (200 mg, crude)as an orange solid. MS (ESI) m/z 625.3 [M+H]+

A mixture of tert-butyl2-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(100 mg, 160 umol, 1.00 eq) 4 M hydrochloride/ethyl acetate (3.00 mL)was stirred at 25° C. for 30 min. The mixture was concentrated todryness. The solution was purified by prep-HPLC and lyophilized toafford crude product which was re-purified by prep-HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.225%FA)-ACN]; B %: 5%-35%, 10 min) and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(pyrrolidin-2-ylethynyl)quinazolin-6-yl)acrylamide(83) (22.23 mg, 37.4 umol, 12% yield, 96% purity, formate) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.9 (br s, 2H), 8.7 (s, 1H), 8.6-8.6(m, 1H), 8.5 (s, 1H), 8.3 (s, 2H), 8.0 (d, J=2.57 Hz, 1H), 7.9 (td,J=7.70, 1.71 Hz, 1H), 7.8 (s, 1H), 7.7 (dd, J=8.93, 2.57 Hz, 1H), 7.6(d, J=7.82 Hz, 1H), 7.4 (dd, J=6.97, 5.38 Hz, 1H), 7.3 (d, J=9.05 Hz,1H), 6.6 (dd, J=17.06, 10.09 Hz, 1H), 6.3 (dd, J=16.99, 1.83 Hz, 1H),5.8-5.9 (m, 1H), 5.3 (s, 2H), 4.1 (br dd, J=7.27, 4.83 Hz, 1H), 3.0-3.0(m, 1H), 2.8 (br dd, J=7.64, 5.07 Hz, 1H), 2.0-2.1 (m, 1H), 1.8-1.9 (m,2H), 1.7-1.7 (m, 1H). MS (ESI) m/z 525.3 [M+H]+

84: A mixture of 3-chloro-3-methylbut-1-yne (2.00 g, 19.5 mmol, 2.19 mL,1.00 eq) and pyrrolidine (4.85 g, 68.3 mmol, 5.70 mL, 3.50 eq) in water(10.0 mL) was stirred for 24 h at 15° C. The mixture was filtered togive the filter cake. The filter cake was dissolved in tert-Butyl methylether (40.0 mL), and washed with brine (35.0 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated under vacuum togive 1-(2-methylbut-3-yn-2-yl)pyrrolidine (0.400 g, 2.91 mmol, 15%yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d₆) δ=3.09 (s, 1H)2.59 (br s, 4H) 1.68 (br s, 4H) 1.30 (s, 6H).

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(6.00 g, 14.1 mmol, 1.00 eq) and potassium acetate (6.91 g, 70.46 mmol,5.00 eq) in dimethyl formamide (20.0 mL) was stirred for 2 h at 100° C.The mixture was concentrated under vacuum to give the residue. Water(50.0 mL) was added to the residue, and the mixture was stirred for 0.5h at room temperature. The mixture was filtered to give the filter cake,which was concentrated under vacuum to give4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-ol(5.60 g, 13.2 mmol, 94% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d₆) δ=9.03 (br s, 1H), 8.60 (br s, 1H), 8.39 (br s, 1H), 8.04 (brs, 1H), 7.88 (br s, 1H), 7.72 (br s, 1H), 7.59 (br s, 1H), 7.37 (br s,1H), 7.25 (br s, 1H), 6.96 (br s, 1H), 5.29 (br s, 2H).

A mixture of4-[3-chloro-4-(2-pyridylmethoxy)anilino]-6-nitro-quinazolin-7-ol (6.00g, 14.16 mmol, 1.00 eq), trifluoromethanesulfonic anhydride (7.99 g,28.31 mmol, 4.67 mL, 2.00 eq) and pyridine (5.60 g, 70.8 mmol, 5.71 mL,5.00 eq) in dichloromethane (50.0 mL) was stirred for 12 h at 25° C. Themixture was concentrated under vacuum to the residue. The residue waspurified by flash to give4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (1.80 g, 3.24 mmol, 23% yield) as a yellowsolid. 1H NMR (400 MHz, DMSO-d₆) δ=10.60 (s, 1H), 9.72 (s, 1H), 8.78 (s,1H), 8.61 (d, J=4.77 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J=2.57 Hz, 1H),7.92-7.87 (m, 1H), 7.70 (dd, J=8.93, 2.57 Hz, 1H), 7.62-7.58 (m, 1H),7.38 (dd, J=6.66, 4.95 Hz, 1H), 7.33 (d, J=9.05 Hz, 1H), 5.32 (s, 2H).

A mixture of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (0.800 g, 1.44 mmol, 1.00 eq),1-(2-methylbut-3-yn-2-yl)pyrrolidine (296 mg, 2.16 mmol, 1.50 eq),copper iodide (137 mg, 720 umol, 0.500 eq), triethylamine (437 mg, 4.32mmol, 601 uL, 3.00 eq) and bis(triphenylphosphine)palladium(II)dichloride (505 mg, 720 umol, 0.500 eq) in dimethyl formamide (8.00 mL)was stirred for 12 h at 25° C. under nitrogen atmosphere. The mixturewas filtered to give the filtrate, which was concentrated under vacuumto give the residue. The residue was purified by flash chromatography[silica gel column: 12 g, petroleum ether/ethyl acetate=1/0-1/1,dichloromethane/methanol=10/1] to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-6-nitroquinazolin-4-amine(0.600 g, 1.10 mmol, 77% yield) as a yellow solid, which was used tonext step directly. MS (ESI) m/z 543.4 [M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-6-nitroquinazolin-4-amin(570 mg, 1.05 mmol, 1.00 eq), iron (293 mg, 5.25 mmol, 5.00 eq),ammonium chloride (281 mg, 5.25 mmol, 184 uL, 5.00 eq) in methanol (20.0mL) and water (4.00 mL) was stirred for 1 h at 70° C. The mixture wasfiltered to give the filtrate, which was concentrated under vacuum togive the residue. The residue was purified by reverse-phasechromatography to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)quinazoline-4,6-diamine(150 mg, 292 umol, 28% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d₆) δ=9.48 (s, 1H), 8.60 (br d, J=4.52 Hz, 1H), 8.34 (s, 1H), 8.05(d, J=2.45 Hz, 1H), 7.92-7.87 (m, 1H), 7.72 (dd, J=8.99, 2.51 Hz, 1H),7.63-7.57 (m, 2H), 7.51 (s, 1H), 7.37 (dd, J=6.85, 5.26 Hz, 1H), 7.25(d, J=9.05 Hz, 1H), 5.46 (s, 2H), 5.29 (s, 2H), 2.73 (br s, 4H),1.76-1.72 (m, 4H) 1.48 (s, 6H).

A mixture ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)quinazoline-4,6-diamine(120 mg, 234 umol, 1.00 eq), acrylic acid (33.7 mg, 468 umol, 32.1 uL,2.00 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(89.7 mg, 468 umol, 2.00 eq), pyridine (37.0 mg, 468 umol, 37.8 uL, 2.00eq) in dimethyl formamide (5.00 mL) was stirred for 1 h at 20° C. Themixture was filtered to give the filtrate. The filtrate was purified byprep-HPLC to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)quinazolin-6-yl)acrylamide(84) (35 mg, 57.09 umol, 24.41% yield, 100% purity, FA) as a yellowsolid. 1H NMR (400 MHz, DMSO-d₆) δ=9.95-9.79 (m, 2H), 8.67-8.55 (m, 3H),8.21 (s, 1H), 8.04 (d, J=2.45 Hz, 1H), 7.89 (td, J=7.70, 1.71 Hz, 1H),7.82 (s, 1H), 7.73 (dd, J=8.99, 2.38 Hz, 1H) 7.59 (d, J=7.83 Hz, 1H),7.38 (dd, J=7.03, 5.20 Hz, 1H), 7.28 (d, J=9.17 Hz, 1H), 6.59-6.48 (m,1H), 6.33 (dd, J=17.12, 1.71 Hz, 1H), 5.85 (dd, J=10.27, 1.59 Hz, 1H),5.30 (s, 2H), 2.69 (br s, 4H), 1.69 (br s, 4H), 1.44 (s, 6H). MS (ESI)m/z 567.4 [M+H]+

85: To a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (2.00g, 10.0 mmol, 1.00 eq) and potassium carbonate (2.77 g, 20.1 mmol, 2.00eq) in methanol (50.0 mL) was added1-diazo-1-dimethoxyphosphoryl-propan-2-one (2.31 g, 12.1 mmol, 1.20 eq)at 25° C. The mixture was stirred at 25° C. for 12 h. The mixture waspartitioned between ethyl acetate (30.0 mL) and water (20.0 mL). Theaqueous phase was extracted with ethyl acetate (2×20.0 mL). The combinedorganic phase was washed with brine (2×10.0 mL), dried with anhydroussodium sulfate, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography to afford tert-butyl3-ethynylpyrrolidine-1-carboxylate (1.80 g, 9.22 mmol, 91% yield) as acolorless oil. 1H NMR (400 MHz, CDCl3) δ=3.71-3.56 (m, 1H), 3.55-3.41(m, 1H), 3.37-3.23 (m, 2H), 2.93 (br s, 1H), 2.20-2.11 (m, 1H),2.19-2.11 (m, 1H), 2.10 (d, J=2.4 Hz, 1H), 1.94 (br d, J=7.0 Hz, 1H),1.45 (s, 9H).

To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (2.36 g, 4.25 mmol, 1.00 eq) inN,N-dimethylformamide (30.0 mL) was added tert-butyl3-ethynylpyrrolidine-1-carboxylate (1.24 g, 6.37 mmol, 1.50 eq),copper(I) iodide (404 mg, 2.12 mmol, 0.500 eq), triethylamine (1.29 g,12.7 mmol, 1.77 mL, 3.00 eq) andtetrakis[triphenylphosphine]palladium(0) (491 mg, 0.425 mmol, 0.100 eq)at 25° C. under nitrogen. The mixture was stirred at 25° C. for 12 h.The mixture was concentrated in vacuum. The residue was purified bysilica gel chromatography to afford tert-butyl3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(720 mg, 1.20 mmol, 28% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.35 (br s, 1H), 9.42 (s, 1H), 8.70 (s, 1H), 8.60 (d, J=4.0Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.95 (s, 1H), 7.88 (dt, J=1.7, 7.7 Hz,1H), 7.70 (dd, J=2.4, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd,J=5.0, 6.5 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 5.30 (s, 2H), 3.62 (br d,J=7.3 Hz, 1H), 3.49-3.40 (m, 2H), 3.36 (br s, 2H), 2.23 (br s, 1H), 2.01(br d, J=7.9 Hz, 1H), 1.42 (s, 9H).

A mixture of tert-butyl3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(620 mg, 1.03 mmol, 1.00 eq) in hydrochloric acid/ethyl acetate (4.00 M,2.00 mL) was stirred at 25° C. for 2 h. The mixture was concentrated invacuum to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(pyrrolidin-3-ylethynyl)quinazolin-4-amine(600 mg, crude, hydrochloric acid) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=11.94 (br s, 1H), 9.82 (s, 1H), 9.63 (br s, 2H), 8.94 (s,1H), 8.75 (d, J=4.5 Hz, 1H), 8.24-8.15 (m, 2H), 7.98 (d, J=2.4 Hz, 1H),7.81 (d, J=7.8 Hz, 1H), 7.73 (dd, J=2.6, 8.9 Hz, 1H), 7.67-7.61 (m, 1H),7.38 (d, J=9.0 Hz, 1H), 5.47 (s, 2H), 3.67-3.52 (m, 2H), 3.41-3.31 (m,1H), 3.30-3.18 (m, 2H), 2.42-2.31 (m, 1H), 2.14-2.02 (m, 1H), 1.91 (s,1H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(pyrrolidin-3-ylethynyl)quinazolin-4-amine(650 mg, 1.21 mmol, 1.00 eq, hydrochloric acid) in acetonitrile (20.0mL) was added formaldehyde (982 mg, 12.1 mmol, 0.901 mL, 10.0 eq),sodium triacetoxy borohydride (820 mg, 3.87 mmol, 3.20 eq). The mixturewas stirred at 25° C. for 12 h. The residue was triturated with water(30.0 mL) and filtered, the filter cake was dried under reduced pressureto affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)ethynyl)-6-nitroquinazolin-4-amine(540 mg, 1.05 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.48-10.36 (m, 1H), 9.50-9.45 (m, 1H), 8.71 (s, 1H), 8.60(d, J=4.3 Hz, 1H), 8.06-7.99 (m, 2H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.72(dd, J=2.3, 8.9 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 7.0Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 5.32-5.29 (m, 2H), 3.60-3.51 (m, 1H),3.40 (br d, J=8.7 Hz, 1H), 3.29-3.26 (m, 1H), 3.15-3.09 (m, 2H), 2.69(s, 3H), 2.45-2.34 (m, 1H), 2.15-2.04 (m, 1H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)ethynyl)-6-nitroquinazolin-4-amine(490 mg, 0.952 mmol, 1.00 eq) and iron powder (372 mg, 6.66 mmol, 7.00eq) in methanol (25.0 mL) was added a solution of ammonium chloride (458mg, 8.56 mmol, 0.299 mL, 9.00 eq) in water (5.00 mL). The mixture wasstirred at 80° C. for 2 h. The residue was added methanol (50.0 mL) andstirred at 55° C. for 0.5 h. After filtration, the filtrate wasconcentrated to afford a residue. The residue was triturated with water(20.0 mL) and saturated sodium carbonate (2.00 mL). After filtration,the filter cake was washed with methanol (50.0 mL). The filtrate wasconcentrated in vacuum to affordN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)ethynyl)quinazoline-4,6-diamine(420 mg, 0.866 mmol, 91% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.46 (br s, 1H), 8.59 (br d, J=4.4 Hz, 1H), 8.32 (s, 1H),8.04 (d, J=2.3 Hz, 1H), 7.93-7.84 (m, 1H), 7.70 (dd, J=2.2, 8.8 Hz, 1H),7.63-7.55 (m, 2H), 7.47 (s, 1H), 7.41-7.33 (m, 1H), 7.24 (d, J=9.0 Hz,1H), 5.67-5.50 (m, 1H), 5.60 (br s, 1H), 5.28 (s, 2H), 3.47-3.35 (m,2H), 3.05 (br t, J=8.6 Hz, 1H), 2.76 (br t, J=7.2 Hz, 2H), 2.43 (s, 3H),2.32-2.24 (m, 1H), 2.09-1.94 (m, 1H).

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)ethynyl)quinazoline-4,6-diamine (370 mg, 0.763 mmol, 1.00 eq), pyridine(121 mg, 1.53 mmol, 0.123 mL, 2.00 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293 mg,1.53 mmol, 2.00 eq) in N,N-dimethylformamide (5.00 mL) was added asolution of acrylic acid (0.500 M, 2.29 mL, 1.50 eq) inN,N-dimethylformamide. The mixture was stirred at 25° C. for 2 h. Themixture was quenched by methanol (2.00 mL) and concentrated in vacuum.The residue was purified by prep-HPLC and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylpyrrolidin-3-yl)ethynyl)quinazolin-6-yl)acrylamide(85) (176.4 mg, 324 umol, 42% yield, 99% purity) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=9.85 (br s, 2H), 8.70 (s, 1H), 8.62-8.58 (m,1H), 8.54 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.88 (dt, J=1.8, 7.7 Hz, 1H),7.78 (s, 1H), 7.71 (dd, J=2.4, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H),7.39-7.34 (m, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.60 (dd, J=10.2, 17.1 Hz,1H), 6.33 (dd, J=1.8, 17.1 Hz, 1H), 5.89-5.80 (m, 1H), 5.29 (s, 2H),3.27-3.21 (m, 2H), 2.87 (t, J=8.3 Hz, 1H), 2.60-2.54 (m, 1H), 2.48 (brd, J=3.5 Hz, 1H), 2.27 (s, 3H), 2.23 (tdd, J=1.8, 4.0, 10.3 Hz, 1H),1.97-1.86 (m, 1H). MS (ESI) m/z 539.4 [M+H]+

86: To a solution of tert-butyl3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(700 mg, 1.16 mmol, 1.00 eq) and iron powder (455 mg, 8.15 mmol, 7.00eq) in methanol (35.0 mL) was added a solution of ammonium chloride (561mg, 10.5 mmol, 0.366 mL, 9.00 eq) in water (7.00 mL). The mixture wasstirred at 80° C. for 2 h. The residue was added methanol (100 mL) andstirred at 55° C. for 0.5 h. After filtration, the filtrate wasconcentrated to afford a residue. The residue was triturated with water(30.0 mL) and saturated sodium carbonate (2.00 mL). After filtration,the filter cake was washed with methanol (100 mL). The filtrate wasconcentrated in vacuum to afford crude product which was purified byprep-HPLC (Phenomenex Synergi C18 150*25*10 um, water (0.1% HCl)-ACN) toafford tert-butyl3-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (280 mg, 0.490 mmol,42% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ=11.30-11.24 (m,1H), 8.73-8.67 (m, 2H), 8.08 (dt, J=1.4, 7.7 Hz, 1H), 7.89 (d, J=2.6 Hz,1H), 7.87-7.79 (m, 1H), 7.76-7.71 (m, 2H), 7.62 (dd, J=2.5, 9.0 Hz, 1H),7.55 (dd, J=5.5, 7.0 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 5.42 (s, 2H),3.70-3.62 (m, 1H), 3.58-3.41 (m, 2H), 3.36-3.21 (m, 2H), 2.24 (br d,J=5.1 Hz, 1H), 2.19-2.04 (m, 1H), 1.64-1.33 (m, 9H).

To a solution of tert-butyl3-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(270 mg, 0.473 mmol, 1.00 eq), pyridine (374 mg, 4.73 mmol, 0.382 mL,10.0 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(906 mg, 4.73 mmol, 10.0 eq) in tetrahydrofuran (10.0 mL) was addedacrylic acid (341 mg, 4.73 mmol, 0.324 mL, 10.0 eq). The mixture wasstirred at 25° C. for 2 h. The mixture was partitioned between ethylacetate (20.0 mL) and water (10.0 mL). The aqueous phase was extractedwith ethyl acetate (2×20.0 mL). The combined organic phase was washedwith brine (2×10.0 mL), dried with anhydrous sodium sulfate, filteredand concentrated in vacuum to afford tert-butyl3-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(450 mg, crude) as a brown oil.

A mixture of tert-butyl3-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate(420 mg, 0.672 mmol, 1.00 eq) in dichloromethane (10.0 mL) was addedtrifluoroacetic acid (3.08 g, 27.0 mmol, 2.00 mL, 40.2 eq). The mixturewas stirred at 25° C. for 0.5 h. The mixture was quenched by methanol(2.00 mL) and concentrated in vacuum. The residue was purified byprep-HPLC and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(pyrrolidin-3-ylethynyl)quinazolin-6-yl)acrylamide(86) (16.46 mg, 26.8 umol, 3% yield, 93% purity, formic acid) as ayellow solid. 1H NMR (400 MHz, DMSO-d6) δ=10.07 (br s, 1H), 9.89 (br s,1H), 8.74 (s, 1H), 8.61-8.58 (m, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.01(d, J=2.4 Hz, 1H), 7.88 (dt, J=1.8, 7.7 Hz, 1H), 7.82 (s, 1H), 7.71 (dd,J=2.2, 8.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.39-7.35 (m, 1H), 7.27 (d,J=9.0 Hz, 1H), 6.66 (br dd, J=10.2, 17.1 Hz, 1H), 6.34 (dd, J=1.8, 17.1Hz, 1H), 5.85 (dd, J=1.8, 10.2 Hz, 1H), 5.29 (s, 2H), 3.30 (br d, J=6.0Hz, 2H), 3.16-3.10 (m, 1H), 3.06 (br s, 2H), 2.18 (br dd, J=6.7, 12.6Hz, 1H), 2.05-1.91 (m, 1H). MS (ESI) m/z 525.3 [M+H]+

87: To a solution of tert-butyl2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)pyrrolidine-1-carboxylate (500 mg, 831 umol, 1.00 eq) in 4 Mhydrochloric acid in ethyl acetate (20.0 mL) was stirred for 0.5 h at25° C. The mixture was concentrated to afford a residue. The residue waspurified by reversed phase (C18, 0.1% HCl in water-MeCN) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(pyrrolidin-2-ylethynyl)quinazolin-4-amine(300 mg, 558 umol, 67% yield, hydrochloride) as a yellow solid. 1H NMR(400 MHz, DMSO-d6) δ=12.0 (br s, 1H), 10.2 (br s, 1H), 10.0 (br s, 1H),9.9 (s, 1H), 8.9 (s, 1H), 8.8 (br d, J=4.52 Hz, 1H), 8.3 (s, 1H), 8.2(brt, J=7.70 Hz, 1H), 8.0 (d, J=2.57 Hz, 1H), 7.8 (d, J=7.82 Hz, 1H),7.7 (dd, J=8.93, 2.45 Hz, 1H), 7.6-7.7 (m, 1H), 7.4 (d, J=9.05 Hz, 1H),5.5 (s, 2H), 4.6-4.9 (m, 1H), 3.2-3.4 (m, 2H), 2.4-2.4 (m, 1H), 2.0-2.1(m, 3H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(pyrrolidin-2-ylethynyl)quinazolin-4-amine(280 mg, 521 umol, 1.00 eq, hydrochloride) and formaldehyde (0.100 M,10.4 mL, 2.00 eq) in acetonitrile (15.0 mL) was added sodiumtriacetoxyhydroborate (220 mg, 1.04 mmol, 2.00 eq) at 20° C. The mixturewas stirred at 20° C. for 1 h. The mixture was concentrated to afford aresidue. The residue was diluted with water (10.0 mL), extracted withethyl acetate (2×20.0 mL). The combined organic layers were washed withwater (10.0 mL), dried over sodium sulfate, filtered and concentrated toafford a residue. The residue was purified by reversed-phase (C18, 0.1%HCl in water-MeCN) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)ethynyl)-6-nitroquinazolin-4-amine(200 mg, 388 umol, 74% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.6 (br s, 1H), 9.6 (s, 1H), 8.7 (s, 1H), 8.6 (br d, J=4.03Hz, 1H), 8.2 (s, 1H), 8.0 (br d, J=2.08 Hz, 1H), 7.9 (td, J=7.67, 1.53Hz, 1H), 7.7-7.8 (m, 1H), 7.6 (br d, J=7.70 Hz, 1H), 7.4 (dd, J=6.85,5.01 Hz, 1H), 7.3 (d, J=9.05 Hz, 1H), 5.3 (s, 2H), 4.7 (br s, 1H),3.4-3.6 (m, 2H), 2.9 (s, 3H), 2.0-2.3 (m, 4H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)ethynyl)-6-nitroquinazolin-4-amine(190 mg, 344 umol, 1.00 eq, hydrochloric acid) and ammonium chloride(207 mg, 3.87 mmol, 135 uL, 11.2 eq) in methanol (6.00 mL) and water(6.00 mL) was added powder iron (168 mg, 3.02 mmol, 8.75 eq) at 20° C.The mixture was heated to 80° C. and stirred at 80° C. for 1 h. Thecombined mixture was concentrated to afford a residue. The residue wasdiluted with water (10.0 mL), saturated sodium carbonate (5.00 mL) andthe mixture was stirred for 30 min. After filtration, the filtrate wasextracted with ethyl acetate (2×30.0 mL) to recover the product. Thecombined organic layer were concentrated to affordN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)ethynyl)quinazoline-4,6-diamine (120 mg, crude) as a brown oil. MS (ESI) m/z485.3 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)ethynyl)quinazoline-4,6-diamine (110 mg, 227 umol, 1.00 eq) and pyridine (0.500M, 907 uL, 2.00 eq) in dimethylformamide (2.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (87.0 mg,454 umol, 2.00 eq) and acrylic acid (0.500 M, 680 uL, 1.50 eq) at 20° C.The mixture was stirred at 20° C. for 2 h. The mixture was purified byprep-HPLC and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylpyrrolidin-2-yl)ethynyl)quinazolin-6-yl)acrylamide (87) (25.02 mg, 46.0 umol, 20% yield, 99%purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.0 (br s, 1H),11.8 (br s, 1H), 10.5 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.8 (d, J=4.77Hz, 1H), 8.2 (s, 1H), 8.2-8.2 (m, 1H), 7.9 (d, J=2.08 Hz, 1H), 7.8 (d,J=7.95 Hz, 1H), 7.7 (br t, J=6.42 Hz, 2H), 7.4 (d, J=9.05 Hz, 1H), 7.2(br dd, J=16.93, 10.21 Hz, 1H), 6.4 (br d, J=17.12 Hz, 1H), 5.9-5.9 (m,1H), 5.9-5.9 (m, 1H), 5.5 (s, 2H), 4.6-4.7 (m, 1H), 3.1-3.3 (m, 2H),2.9-3.0 (m, 3H), 2.0-2.3 (m, 4H). MS (ESI) m/z 539.3 [M+H]+

88: A reaction mixture of tert-butyl (2-methylbut-3-yn-2-yl)carbamate(2.50 g, 13.6 mmol, 1.00 eq), iodomethane (3.87 g, 27.3 mmol, 1.70 mL,2.00 eq) and sodium hydride (1.09 g, 27.3 mmol, 60% purity, 2.00 eq) indimethyl formamide (10.0 mL) was stirred for 2 h at 0° C. Water (20.0mL) was added to the mixture and extracted with ethyl acetate (3×50.0mL). The organic layers were washed with brine (3×20.0 mL), dried oversodium sulfate, filtered and concentrated under vacuum to give the crudeproduct. The crude product was purified by flash chromatography [silicagel column: 40 g, petroleum ether/ethyl acetate=10/1] to give tert-butylmethyl(2-methylbut-3-yn-2-yl)carbamate (1.30 g, 6.59 mmol, 48% yield) ascolorless oil. 1H NMR (400 MHz, CDCl3) δ=2.92 (s, 3H), 2.30 (s, 1H),1.59 (s, 6H), 1.41 (s, 9H).

A reaction mixture of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (900 mg, 1.62 mmol, 1.00 eq), tert-butylmethyl(2-methylbut-3-yn-2-yl)carbamate (639 mg, 3.24 mmol, 2.00 eq),copper iodide (154 mg, 809 umol, 0.500 eq),tetrakis(triphenylphosphine)palladium (374 mg, 324 umol, 0.200 eq) andtriethylamine (328 mg, 3.24 mmol, 451 uL, 2.00 eq) in dimethyl formamide(15.0 mL) was stirred for 12 h at 25° C. The mixture was concentratedunder vacuum to give the residue. The residue was purified by flashchromatography [silica gel column: 20 g; petroleum ether/ethylacetate=10/1-1/1] to give tert-butyl(4-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate(580 mg, 962 umol, 59% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.36 (s, 1H), 9.45 (s, 1H), 8.71 (s, 1H), 8.61 (br d, J=4.03Hz, 1H), 8.01 (d, J=2.57 Hz, 1H), 7.92 (s, 1H), 7.90-7.86 (m, 1H), 7.71(dd, J=8.99, 2.51 Hz, 1H), 7.61-7.59 (m, 1H), 7.38 (dd, J=7.15, 5.07 Hz,1H), 7.31 (d, J=9.05 Hz, 1H), 5.31 (s, 2H), 2.74 (s, 3H), 1.73 (s, 6H),1.43 (s, 9H).

A reaction mixture of tert-butyl(4-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate(600 mg, 995 umol, 1.00 eq), iron power (278 mg, 4.97 mmol, 5.00 eq) andammonium chloride (266 mg, 4.97 mmol, 5.00 eq) in methanol (20.0 mL) andwater (4.00 mL) was stirred for 1 h at 70° C. The mixture was filteredto give the filtrate, which was concentrated under vacuum to give theresidue. The residue was purified by prep-HPLC to give tert-butyl(4-(6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate(160 mg, 279 umol, 28% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.46 (s, 1H), 8.60 (br d, J=4.40 Hz, 1H), 8.32 (s, 1H), 8.04(d, J=2.08 Hz, 1H), 7.94-7.86 (m, 1H), 7.70 (dd, J=8.93, 1.96 Hz, 1H),7.59 (br d, J=8.07 Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.40-7.36 (m,1H), 7.25 (d, J=9.17 Hz, 1H), 5.80 (br s, 2H), 5.29 (s, 2H), 2.94 (s,3H), 1.71 (s, 6H), 1.46 (s, 9H).

A mixture of tert-butyl(4-(6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate(170 mg, 297 umol, 1.00 eq), acrylic anhydride (44.9 mg, 356 umol, 4.79uL, 1.20 eq), and triethylamine (60.0 mg, 593 umol, 82.6 uL, 2.00 eq) indimethyl formamide (4.00 mL) was stirred for 1 h at 22° C. The mixturewas filtered to give the filtrate. The filtrate was purified byprep-HPLC to give tert-butyl(4-(6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate(62 mg, 98.86 umol, 33.33% yield) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ=9.68 (s, 1H), 9.25 (s, 1H), 8.67 (s, 1H), 8.62 (br d, J=4.28Hz, 1H), 8.03 (s, 1H), 7.93 (d, J=2.57 Hz, 1H), 7.89 (s, 1H), 7.80-7.74(m, 1H), 7.69 (d, J=7.82 Hz, 1H), 7.56 (dd, J=8.86, 2.63 Hz, 1H),7.31-7.23 (m, 3H), 7.13 (dd, J=16.93, 10.21 Hz, 1H), 7.03 (d, J=8.80 Hz,1H), 6.56 (dd, J=16.93, 1.53 Hz, 1H), 5.87-5.76 (m, 1H), 5.32 (s, 2H),2.97 (s, 3H), 1.75 (s, 6H), 1.50 (s, 9H).

A reaction mixture of tert-butyl(4-(6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)(methyl)carbamate (57.0 mg,90.9 umol, 1.00 eq) and trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00mL, 149 eq) in dichloromethane (5.00 mL) was stirred for 1 h at 0° C.The mixture was concentrated under vacuum to give the residue. Theresidue was purified by prep-HPLC to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(3-methyl-3-(methylamino)but-1-yn-1-yl)quinazolin-6-yl)acrylamide88 (16.73 mg, 29.20 umol, 32.12% yield, 100% purity, FA) as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) δ=9.88 (s, 1H), 9.80 (s, 1H), 8.71 (s,1H), 8.61 (br d, J=4.77 Hz, 1H), 8.57 (s, 1H), 8.25 (s, 1H), 8.03 (s,1H), 7.89 (t, J=7.58 Hz, 1H), 7.78 (s, 1H), 7.72 (br d, J=9.17 Hz, 1H),7.59 (d, J=7.82 Hz, 1H), 7.41-7.36 (m, 1H), 7.28 (d, J=8.68 Hz, 1H),6.59 (br dd, J=16.63, 10.15 Hz, 1H), 6.34 (br d, J=17.12 Hz, 1H), 5.85(br d, J=10.03 Hz, 1H), 5.30 (s, 2H), 2.36 (s, 3H), 1.38 (s, 6H). MS(ESI) m/z 527.3 [M+H]+

89: To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)quinazoline-4,6-diamine(50.0 mg, 92.2 umol, 1.00 eq) and but-2-ynoic acid (15.5 mg, 184 umol,2.00 eq) in pyridine (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.7 mg,369 umol, 4.00 eq) at 25° C. The mixture was stirred at 25° C. for 0.5h. The reaction mixture was filtered. The filtrate was purified byprep-HPLC (column: X timate C18 150*25 mm*5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)−ACN]; B %: 51%-81%, 10 min) to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)quinazolin-6-yl)but-2-ynamide89 (4.91 mg, 8.07 umol, 9% yield, 100% purity) as a white solid. 1H NMR(400 MHz, CDCl3) δ=8.88 (s, 1H), 8.68 (s, 1H), 8.62 (d, J=4.2 Hz, 1H),8.48 (s, 1H), 7.95 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.87 (s, 1H), 7.78(d, J=1.8 Hz, 1H), 7.72-7.66 (m, 1H), 7.54 (dd, J=8.9, 2.6 Hz, 1H), 7.26(br d, J=6.6 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 5.32 (s, 2H), 2.84 (br s,4H), 2.57 (br s, 4H), 2.33 (s, 3H), 2.07 (s, 3H), 1.61 (s, 6H). MS (ESI)m/z 608.4 [M+H]+90: The reaction mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(0.800 g, 1.88 mmol, 1.00 eq), tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate (816 mg, 3.76 mmol, 2.00 eq)and potassium tert-butoxide (632 mg, 5.64 mmol, 3.00 eq) indimethylsulfoxide (10.0 mL) was stirred for 1 h at 25° C. The mixturewas filtered to give the filtrate. The filtrate was purified byreverse-phase chromatography [column: 80 g; CH3CN/H2O (FA:0.1%)=0/1-1/2] to give tert-butyl3-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(900 mg, 1.44 mmol, 77% yield) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ=9.03 (br s, 1H), 8.60 (br d, J=4.65 Hz, 1H), 8.53 (s, 2H),7.91-7.86 (m, 1H), 7.84 (br s, 1H), 7.59 (d, J=7.70 Hz, 1H), 7.44 (br s,1H), 7.39-7.35 (m, 1H), 7.31 (br s, 1H), 7.16 (br d, J=8.93 Hz, 1H),5.25 (s, 2H), 4.56-4.47 (m, 1H), 4.43-4.29 (m, 1H), 4.24 (br s, 1H),3.99 (br d, J=11.62 Hz, 1H), 3.83 (br d, J=10.88 Hz, 1H), 3.68 (br s,1H), 3.53 (br d, J=9.29 Hz, 1H), 3.41 (br s, 2H), 1.36 (br s, 9H).

A reaction mixture of tert-butyl3-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(1.00 g, 1.60 mmol, 1.00 eq), ammonium chloride (429 mg, 8.02 mmol, 281uL, 5.00 eq) and iron (448 mg, 8.02 mmol, 5.00 eq) in methanol (15.0 mL)and water (4.00 mL) was stirred for 1 h at 70° C. The mixture wasfiltered to give the filtrate. The filtrate was purified byreverse-phase chromatography [column: 80 g: CH3CN/H2O(NH3.H2O:0.1%)=0/1-1/1] to givetert-butyl3-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(150 mg, 253 umol, 16% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.26 (s, 1H), 8.60 (d, J=4.63 Hz, 1H), 8.33 (s, 1H), 8.05 (d,J=2.50 Hz, 1H), 7.89 (td, J=7.69, 1.75 Hz, 1H), 7.71 (dd, J=9.01, 2.50Hz, 1H), 7.59 (d, J=7.75 Hz, 1H), 7.42-7.34 (m, 2H), 7.23 (d, J=9.13 Hz,1H), 7.17 (br s, 1H), 5.33 (s, 2H), 5.28 (s, 2H), 4.44-4.26 (m, 3H),4.05 (d, J=11.88 Hz, 1H), 3.84 (br d, J=9.38 Hz, 1H), 3.68 (br s, 1H),3.55 (br d, J=10.63 Hz, 1H), 3.45-3.37 (m, 1H), 3.22 (br s, 1H), 1.41(br s, 9H).

A reaction mixture of tert-butyl3-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate (100 mg, 169 umol,1.00 eq), acrylic acid (24.3 mg, 337 umol, 23.1 uL, 2.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64.7 mg,337 umol, 2.00 eq) and pyridine (40.0 mg, 506 umol, 40.8 uL, 3.00 eq) indimethyl formamide (5.00 mL) was stirred for 1 h at 20° C. The mixturewas filtered to give the filtrate. The filtrate was purified byprep-HPLC {column: Waters Xbridge 150*25 5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)−ACN]; B %: 48%-78%, 10 min.} to givetert-butyl 3-(((6-acrylamido-4-((3-chloro4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate(40.0 mg, 61.8 umol, 37% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.71 (s, 1H), 9.43 (s, 1H), 8.98 (br s, 1H), 8.61 (d, J=4.77Hz, 1H), 8.50 (s, 1H), 7.99 (d, J=2.57 Hz, 1H), 7.89 (td, J=7.70, 1.71Hz, 1H), 7.70 (dd, J=8.99, 2.38 Hz, 1H), 7.60 (d, J=7.82 Hz, 1H),7.43-7.35 (m, 2H), 7.26 (d, J=9.05 Hz, 1H), 6.72 (dd, J=16.93, 10.21 Hz,1H), 6.34 (br d, J=16.63 Hz, 1H), 5.85 (br d, J=9.90 Hz, 1H), 5.29 (s,2H), 4.51 (br s, 1H), 4.35 (br s, 2H), 4.08 (d, J=11.98 Hz, 1H), 3.85(br d, J=8.93 Hz, 1H), 3.70 (br d, J=11.49 Hz, 1H), 3.55 (br d, J=10.88Hz, 1H), 3.46-3.35 (m, 2H), 1.39 (br s, 9H).

A reaction mixture of tert-butyl3-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)morpholine-4-carboxylate (30.0 mg, 46.4 umol,1.00 eq) and trifluoroacetic acid (308 mg, 2.70 mmol, 0.200 mL, 58.3 eq)in dichloromethane (1.00 mL) was stirred for 1 h at 0° C. and thenstirred for 0.5 h at 20° C. The mixture was concentrated under vacuum togive the residue. The residue was purified by prep-HPLC HPLC {column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−ACN]; B %: 21/6-51%, 10 min.} to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(morpholin-3-ylmethoxy)quinazolin-6-yl)acrylamide 90 (11 mg,19.71 umol, 42.51% yield, 98% purity) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ=9.71 (br d, J=5.99 Hz, 2H), 8.89 (s, 1H), 8.61 (d,J=4.16 Hz, 1H), 8.50 (s, 1H), 8.00 (d, J=2.57 Hz, 1H), 7.89 (td, J=7.70,1.71 Hz, 1H), 7.70 (dd, J=8.99, 2.51 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H),7.38 (dd, J=6.91, 4.95 Hz, 1H), 7.29-7.24 (m, 2H), 6.76 (dd, J=16.99,10.27 Hz, 1H), 6.34 (dd, J=16.99, 1.83 Hz, 1H), 5.89-5.82 (m, 1H), 5.29(s, 2H), 4.20-4.14 (m, 1H), 4.12-4.05 (m, 1H), 3.90 (dd, J=10.70, 2.38Hz, 1H), 3.74 (br d, J=11.37 Hz, 1H), 3.51-3.42 (m, 1H), 3.28-3.20 (m,2H), 2.95-2.80 (m, 2H). MS (ESI) m/z 547.4 [M+H]+

91: To a solution of 7-fluoro-6-nitroquinazolin-4-ol (5.00 g, 23.9 mmol,1.00 eq) in thionyl chloride (80.0 mL) was added dimethyl formamide (175mg, 2.39 mmol, 184 uL, 0.100 eq) at 25° C. The mixture was stirred at90° C. for 12 h. The reaction mixture was concentrated under reducedpressure to give 4-chloro-7-fluoro-6-nitroquinazoline (5.00 g, crude) asa light yellow solid.

To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.00 g, 17.1 mmol,1.00 eq) in dimethylsulfoxide (40.0 mL) was added potassium carbonate(4.72 g, 34.2 mmol, 2.00 eq) and phenol (1.77 g, 18.8 mmol, 1.65 mL,1.10 eq). The mixture was stirred at 80° C. for 2 h. The reactionmixture was added water (100 mL) and extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (50 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure togive 2-chloro-4-nitro-1-phenoxybenzene (5.00 g, crude) as yellow oil. 1HNMR (400 MHz, CDCl3) δ=8.34-8.25 (m, 1H), 8.01-7.90 (m, 1H), 7.42-7.33(m, 2H), 7.25-7.17 (m, 1H), 7.04-6.96 (m, 2H), 6.80 (d, J=9.0 Hz, 1H).

To a solution of 2-chloro-4-nitro-1-phenoxybenzene (5.00 g, 20.0 mmol,1.00 eq) in water (30.0 mL) and methanol (150 mL) was added ammoniumchloride (9.64 g, 180 mmol, 6.30 mL, 9.00 eq) and iron powder (5.59 g,100 mmol, 5.00 eq) in portions. The mixture was stirred at 80° C. for 2h. The mixture was added methanol (200 mL) and filtered. The filtratewas concentrated to give crude product. The crude product was dilutedwith water (100 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layer was washed with brine (50 mL) and dried oversodium sulfate, filtered and concentrated to give3-chloro-4-phenoxyaniline (4.70 g, crude) as yellow oil. 1H NMR (400MHz, CDCl3) δ=7.25-7.18 (m, 2H), 6.99-6.91 (m, 1H), 6.86-6.78 (m, 3H),6.70 (d, J=2.8 Hz, 1H), 6.48 (dd, J=2.8, 8.6 Hz, 1H), 3.95-3.11 (m, 2H).

To a solution of 4-chloro-7-fluoro-6-nitroquinazoline (3.00 g, 13.2mmol, 1.00 eq) in isopropyl alcohol (50.0 mL) was added3-chloro-4-phenoxyaniline (3.19 g, 14.5 mmol, 1.10 eq) in one portion at20° C. The mixture was stirred at 80° C. for 2 h. The reaction mixturewas concentrated under reduced pressure to giveN-(3-chloro-4-phenoxyphenyl)-7-fluoro-6-nitroquinazolin-4-amine (4.70 g,11.4 mmol, 87% yield) as a white solid. MS (ESI) m/z 410.9 [M+H]+; 1HNMR (400 MHz, DMSO-d6) δ=9.66 (br d, J=7.2 Hz, 1H), 8.87-8.79 (m, 1H),8.18 (br s, 1H), 7.89 (br d, J=12.4 Hz, 1H), 7.85-7.77 (m, 1H), 7.42 (t,J=8.0 Hz, 2H), 7.23 (d, J=9.0 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.00 (d,J=8.6 Hz, 2H).

To a solution ofN-(3-chloro-4-phenoxyphenyl)-7-fluoro-6-nitroquinazolin-4-amine (2.00 g,4.87 mmol, 1.00 eq), (R)-1-methylpyrrolidin-3-ol (985 mg, 9.74 mmol,1.07 mL, 2.00 eq) in dimethylsulfoxide (25.0 mL) was added potassiumtert-butoxide (1.64 g, 14.6 mmol, 3.00 eq). The mixture was stirred at20° C. for 12 h. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (50 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give(R)—N-(3-chloro-4-phenoxyphenyl)-7-((1-methylpyrrolidin-3-yl)oxy)-6-nitroquinazolin-4-amine(2.00 g, crude) as a yellow solid. MS (ESI) m/z 492.1 [M+H]+

To a solution of(R)—N-(3-chloro-4-phenoxyphenyl)-7-((1-methylpyrrolidin-3-yl)oxy)-6-nitroquinazolin-4-amine(2.00 g, 4.07 mmol, 1.00 eq) and ammonium chloride (1.96 g, 36.6 mmol,1.28 mL, 9.00 eq) in water (4.00 mL) and methanol (20.0 mL) was addediron powder (1.59 g, 28.5 mmol, 7.00 eq) in one portion. The mixture wasstirred at 80° C. for 1 h. The mixture was added methanol (50 mL) andfiltered. The filtrate was concentrated to give a residue. The residuewas purified by prep-HPLC (column: Phenomenex luna C18 150*25 10 u;mobile phase: [water (0.225% FA)-ACN]; B %: 16%-36%, 7.8 min) to give(R)—N4-(3-chloro-4-phenoxyphenyl)-7-((1-methylpyrrolidin-3-yl)oxy)quinazoline-4,6-diamine(1.00 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.42 (brs, 1H), 8.39 (s, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.15 (s, 1H), 7.85 (dd,J=2.6, 9.0 Hz, 1H), 7.43 (s, 1H), 7.41-7.35 (m, 2H), 7.18 (d, J=9.0 Hz,1H), 7.11 (t, J=7.4 Hz, 1H), 7.05 (s, 1H), 6.98-6.87 (m, 2H), 5.43 (brs, 2H), 5.20 (br d, J=3.8 Hz, 1H), 3.13 (br d, J=3.0 Hz, 2H), 3.10-2.99(m, 2H), 2.79-2.69 (m, 1H), 2.53 (s, 3H), 2.09-2.01 (m, 1H). MS (ESI)m/z 462.1 [M+H]+

To a solution of(R)-N4-(3-chloro-4-phenoxyphenyl)-7-((1-methylpyrrolidin-3-yl)oxy)quinazoline-4,6-diamine(0.300 g, 649 umol, 1.00 eq) and acrylic anhydride (123 mg, 974 umol,6.69 uL, 1.50 eq) in dimethyl formamide (2.00 mL) was addedtriethylamine (131 mg, 1.30 mmol, 181 uL, 2.00 eq) dropwise at 25° C.The mixture was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC (column: Xtimate C18150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN];B %: 50%-80%, 10 min) and prep-HPLC (column: Xtimate C18 150*25 mm*5 um;mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN]; B %: 50%-80%,10 min) and lyophilized to give(R)—N-(4-((3-chloro-4-phenoxyphenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)acrylamide 91 (69.38 mg, 133 umol, 21% yield, 99%purity, 99% ee) as a white solid. 1H NMR (400 MHz, CDCl3) δ=9.15 (s,1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.90 (s, 1H),7.60 (dd, J=8.8, 2.6 Hz, 1H), 7.39-7.33 (m, 2H), 7.19 (s, 1H), 7.14-7.09(m, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.01 (dd, J=8.6, 1.0 Hz, 2H), 6.55-6.40(m, 2H), 5.87-5.80 (m, 1H), 5.09 (br t, J=6.0 Hz, 1H), 3.19 (d, J=11.0Hz, 1H), 3.11 (td, J=8.8, 3.4 Hz, 1H), 2.67 (dd, J=11.0, 5.2 Hz, 1H),2.60-2.50 (m, 1H), 2.47 (s, 3H), 2.37 (q, J=8.4 Hz, 1H), 2.22-2.10 (m,1H). MS (ESI) m/z 516.1 [M+H]+

92: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine(1.00 g, 2.06 mmol, 1.00 eq), tert-butylhexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (654 mg, 3.08 mmol,1.50 eq), potassium carbonate (1.14 g, 8.23 mmol, 4.00 eq) and potassiumiodide (341 mg, 2.06 mmol, 1.00 eq) in acetonitrile (10.0 mL) wasstirred at 110° C. for 12 h. The reaction mixture was concentrated togive a residue. The residue was triturated with water (20.0 mL) to givetert-butyl4-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (1.20 g, 1.81 mmol, 88% yield) as a yellowsolid. MS (ESI) m/z 662.4 [M+H]+

A mixture of tert-butyl4-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (1.00 g, 1.51mmol, 1.00 eq), 2,2,2-trifluoroacetic acid (3.08 g, 27.0 mmol, 17.9 eq)in dichloromethane (10.0 mL) was stirred at 25° C. for 12 h. Thereaction mixture was concentrated to give a residue. The residue waspurified by prep-HPLC {column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-40%, 18 min, 50%min} and lyophilized to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)-6-nitroquinazolin-4-amine(700 mg, 1.25 mmol, 82% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.10 (br s, 1H), 9.22 (s, 1H), 8.64 (s, 1H), 8.62-8.59 (m,1H), 8.19 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H),7.70 (dd, J=2.5, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.38(dd, J=5.3, 7.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 5.31 (s, 2H), 4.48-4.33(m, 2H), 4.14-4.07 (m, 1H), 3.26-3.20 (m, 2H), 3.15-3.06 (m, 2H), 2.80(td, J=4.6, 13.8 Hz, 1H), 2.53 (br s, 1H), 2.38-2.26 (m, 1H), 2.26-2.14(m, 1H), 1.92 (br dd, J=5.5, 13.3 Hz, 1H), 1.85-1.69 (m, 2H). MS (ESI)m/z 562.1 [M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)-6-nitroquinazolin-4-amine(500 mg, 889 umol, 1.00 eq) and formaldehyde (285 mg, 8.90 mmol, 360 uL,10.0 eq) and sodium borohydride (33.7 mg, 889 umol, 1.00 eq) in2,2,2-trifluoroethanol (6.00 mL) was stirred at 40° C. for 12 h. Thereaction mixture was concentrated to give a residue. The residue waspurified by Reverse-MPLC on Xtimate C-18(20/40 um, 120A) gel eluted withH2O (0.1% FA:): MeCN (20/1 to 1/5) and lyophilized to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)-6-nitroquinazolin-4-amine(500 mg, 868 umol, 97% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.07 (br s, 1H), 9.23-9.17 (m, 1H), 8.66-8.55 (m, 2H), 8.19(s, 2H), 8.01 (d, J=2.4 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd,J=2.4, 8.9 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.37 (dd,J=5.1, 7.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 5.30 (s, 2H), 4.41-4.33 (m,2H), 3.50-3.19 (m, 2H), 3.09-2.95 (m, 2H), 2.51 (br s, 3H), 2.45 (br d,J=17.4 Hz, 4H), 1.96-1.79 (m, 2H), 1.77-1.49 (m, 2H). MS (ESI) m/z 576.2[M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)-6-nitroquinazolin-4-amine(500 mg, 867 umol, 1.00 eq), iron (242 mg, 4.34 mmol, 5.00 eq) andammonium chloride (417 mg, 7.81 mmol, 9.00 eq) in methanol (5.00 mL) andwater (1.00 mL) was stirred at 80° C. for 12 h. To the mixture was addedmethanol (50.0 mL). The mixture was filtered. The filtrate wasconcentrated to give a residue. The residue was purified by prep-HPLC{column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.04%NH3H2O+10 mM NH4HCO3)-ACN]; B %: 36%-66%, 43 min} and lyophilized togiveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)quinazoline-4,6-diamine(70.0 mg, 128 umol, 15% yield) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ=8.52 (br d, J=4.3 Hz, 1H), 8.47 (s, 1H), 7.76 (d, J=2.4 Hz,1H), 7.68 (br t, J=6.9 Hz, 1H), 7.62-7.57 (m, 1H), 7.40 (dd, J=2.4, 8.8Hz, 1H), 7.18-7.15 (m, 1H), 7.08 (s, 1H), 6.96-6.92 (m, 1H), 6.88 (br s,1H), 6.84 (s, 1H), 5.22 (s, 2H), 4.20 (br t, J=5.6 Hz, 2H), 3.16-3.08(m, 2H), 3.05-2.94 (m, 2H), 2.87-2.75 (m, 2H), 2.46 (q, J=8.0 Hz, 1H),2.33-2.32 (m, 1H), 2.23 (s, 3H), 1.79 (br s, 4H).

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)quinazoline-4,6-diamine (60.0 mg, 109umol, 1.00 eq), pyridine (34.7 mg, 439 umol, 4.00 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (84.3 mg, 439 umol, 4.00eq) in dimethyl formamide (1.00 mL) was added acrylic acid (11.9 mg, 164umol, 1.50 eq) at 25° C. The mixture was stirred at 25° C. for 0.5 h.The reaction mixture was filtered. The filtrate was purified byprep-HPLC {column: Xtimate C18 150*25 mm*5 um; mobile phase. [water(0.05% ammonia hydroxide v/v)−ACN]; B %: 51%-81%, 10 min} andlyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)ethoxy)quinazolin-6-yl)acrylamide92 (25.96 mg, 42.3 umol, 38% yield, 98% purity) as a white solid. 1H NMR(400 MHz, CDCl3) δ=9.20 (s, 1H), 9.11 (s, 1H), 8.65 (s, 1H), 8.62 (d,J=4.3 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.81-7.74 (m, 1H), 7.68 (br d,J=10.5 Hz, 2H), 7.53 (dd, J=2.6, 8.9 Hz, 1H), 7.26 (s, 2H), 7.02 (d,J=8.8 Hz, 1H), 6.69-6.43 (m, 2H), 5.97-5.76 (m, 1H), 5.32 (s, 2H),4.37-4.27 (m, 2H), 3.27-3.16 (m, 2H), 3.15-3.04 (m, 2H), 2.93-2.83 (m,2H), 2.59-2.49 (m, 1H), 2.36 (dt, J=7.0, 9.5 Hz, 1H), 2.32 (s, 3H),1.92-1.87 (m, 2H), 1.87-1.77 (m, 2H). MS (ESI) m/z 600.3 [M+H]+

93: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.00 g, 2.35 mmol, 1.00 eq), N,N-dimethylazetidin-3-amine (481 mg, 3.52mmol, 1.50 eq, HCl) and potassium carbonate (1.30 g, 9.39 mmol, 4.00 eq)in dimethylsulfoxide (20.0 mL) was stirred at 25° C. for 12 h. To thereaction mixture was added of water (20.0 mL). The mixture was filtered.The filter cake was dried to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)azetidin-1-yl)-6-nitroquinazolin-4-amine(1.00 g, 1.98 mmol, 84% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.98 (br s, 1H), 9.12 (s, 1H), 8.60 (br d, J=4.4 Hz, 1H),8.49 (s, 1H), 8.02 (br s, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.70 (br d, J=8.8Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.43-7.33 (m, 1H), 7.27 (d, J=9.0 Hz,1H), 6.78 (s, 1H), 5.30 (s, 2H), 4.04 (br t, J=7.9 Hz, 2H), 3.79 (br dd,J=5.0, 8.8 Hz, 2H), 3.23-3.12 (m, 1H), 2.13 (s, 6H). MS (ESI) m/z 506.1[M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)azetidin-1-yl)-6-nitroquinazolin-4-amine (900 mg, 1.78 mmol, 1.00 eq),iron (496 mg, 8.89 mmol, 5.00 eq), ammonium chloride (856 mg, 16.0 mmol,9.00 eq) in methanol (20.0 mL) and water (5.00 mL) was stirred at 80° C.for 1 h. To the mixture was added methanol (50.0 mL). The reactionmixture was filtered. The filtrate was concentrated to give a residue.The residue was triturated with saturated sodium carbonate (10.0 mL) togiveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)azetidin-1-yl)quinazoline-4,6-diamine(600 mg, 1.26 mmol, 71% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.09 (s, 1H), 8.53 (br d, J=4.3 Hz, 1H), 8.21 (s, 1H), 7.97(br d, J=2.3 Hz, 1H), 7.85-7.76 (m, 1H), 7.62 (br dd, J=2.1, 8.9 Hz,1H), 7.52 (br d, J=7.7 Hz, 1H), 7.35-7.22 (m, 2H), 7.14 (br d, J=8.9 Hz,1H), 6.55 (s, 1H), 5.20 (s, 2H), 4.80 (br s, 2H), 4.08 (br t, J=7.2 Hz,2H), 3.61 (br t, J=6.7 Hz, 2H), 3.07-2.99 (m, 1H), 2.05 (s, 6H). MS(ESI) m/z 476.3 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(3-(dimethylamino)azetidin-1-yl) quinazoline-4,6-diamine (300 mg, 630 umol, 1.00 eq),pyridine (199 mg, 2.52 mmol, 4.00 eq) and acrylic acid (54.5 mg, 756umol, 51.9 uL, 1.20 eq) in dimethyl formamide (2.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (362 mg, 1.89 mmol, 3.00eq) at 25° C. The mixture was stirred at 25° C. for 0.5 h. The reactionmixture was filtered. The filtrate was purified by prep-HPLC {column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−ACN]; B %: 20%-50%, 10 min} and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(3-(dimethylamino)azetidin-1-yl)quinazolin-6-yl)acrylamide93 (84.35 mg, 159 umol, 25% yield, 100% purity) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=9.76 (s, 1H), 9.49 (s, 1H), 8.76-8.54 (m, 1H),8.43 (s, 1H), 8.26 (s, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.8, 7.7Hz, 1H), 7.72 (dd, J=2.6, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37(ddd, J=1.0, 4.9, 7.5 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 6.63 (s, 1H),6.53 (dd, J=10.3, 17.1 Hz, 1H), 6.30 (dd, J=1.9, 17.1 Hz, 1H), 5.81 (dd,J=1.7, 10.3 Hz, 1H), 5.28 (s, 2H), 4.09 (t, J=7.5 Hz, 2H), 3.77 (dd,J=5.6, 7.9 Hz, 2H), 3.14 (quin, J=6.2 Hz, 1H), 2.10 (s, 6H). MS (ESI)m/z 530.1 [M+H]+

94: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.00 g, 2.35 mmol, 1.00 eq) and potassium tert-butoxide (791 mg, 7.05mmol, 3.00 eq) in dimethylsulfoxide (10.0 mL) was added2-(dimethylamino)-2-methyl-propan-1-ol (551 mg, 4.70 mmol, 2.00 eq) at25° C. The mixture was stirred at 25° C. for 2 h. The reaction wasquenched by water (30.0 mL). The mixture was partitioned between ethylacetate (50.0 mL) and water (30.0 mL). The aqueous phase was extractedwith ethyl acetate (2/20.0 mL). The combined organic phase was washedwith brine (2×20.0 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuum to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(dimethylamino)-2-methylpropoxy)-6-nitroquinazolin-4-amine(950 mg, 1.82 mmol, 77% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d6) δ=10.06 (s, 1H), 9.21 (s, 1H), 8.62 (s, 1H), 8.61-8.59 (m, 1H),8.01 (d, J=2.6 Hz, 1H), 7.89-7.86 (m, 1H), 7.70 (dd, J=2.6, 8.9 Hz, 1H),7.58 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.38-7.35 (m, 1H), 7.28 (d, J=9.0Hz, 1H), 5.30 (s, 2H), 2.25 (s, 6H), 1.51-1.46 (m, 2H), 1.13 (s, 6H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(dimethylamino)-2-methylpropoxy)-6-nitroquinazolin-4-amine(950 mg, 1.82 mmol, 1.00 eq) and iron powder (710 mg, 12.7 mmol, 7.00eq) in methanol (50.0 mL) was added a solution of ammonium chloride (875mg, 16.4 mmol, 0.572 mL, 9.00 eq) in water (10.0 mL). The mixture wasstirred at 80° C. for 2 h. The residue was added methanol (100 mL) andstirred at 55° C. for 0.5 h. After filtration, the filtrate wasconcentrated to afford a residue. The residue was triturated with water(30.0 mL) and saturated sodium carbonate (3.00 mL). After filtration,the filter cake was washed with methanol (100 mL). The filtrate wasconcentrated in vacuum to affordN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(dimethylamino)-2-methylpropoxy)quinazoline-4,6-diamine(800 mg, 1.62 mmol, 89% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d6) δ=10.77 (br s, 1H), 9.50 (br s, 1H), 8.59 (br d, J=4.4 Hz, 1H),8.37 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.70 (br dd,J=2.3, 8.9 Hz, 1H), 7.58 (br d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.23 (br d,J=8.9 Hz, 1H), 7.14 (s, 1H), 5.28 (s, 2H), 4.33 (s, 2H), 2.73 (s, 6H),1.47 (s, 6H).

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(dimethylamino)-2-methylpropoxy)quinazoline-4,6-diamine (300 mg, 0.609 mmol, 1.00 eq), pyridine (96.3mg, 1.22 mmol, 0.0982 mL, 2.00 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (233 mg,1.22 mmol, 2.00 eq) in N,N-dimethylformamide (3.00 mL) was added asolution of acrylic acid (0.500 M, 1.83 mL, 1.50 eq) inN,N-dimethylformamide. The mixture was stirred at 25° C. for 2 h. Themixture was quenched by methanol (2.00 mL) and concentrated in vacuum.The residue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN]; B %:38%-68%, 10 min) and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(dimethylamino)-2-methylpropoxy)quinazolin-6-yl)acrylamide94 (49.51 mg, 87.8 umol, 14% yield, 97% purity) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=9.67 (s, 1H), 9.62 (s, 1H), 8.70 (s, 1H),8.62-8.58 (m, 1H), 8.51 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.88 (dt,J=1.7, 7.7 Hz, 1H), 7.71 (dd, J=2.6, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz,1H), 7.37 (dd, J=4.9, 6.5 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=9.0 Hz, 1H),6.57 (dd, J=10.2, 16.9 Hz, 1H), 6.30 (dd, J=1.9, 17.1 Hz, 1H), 5.86-5.76(m, 1H), 5.29 (s, 2H), 4.06 (s, 2H), 2.25 (s, 6H), 1.13 (s, 6H). MS(ESI) m/z 547.4 [M+1]+

95: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.30 g, 3.05 mmol, 1.00 eq) and 2-(1-methylpyrrolidin-2-yl)ethanol (789mg, 6.11 mmol, 830 uL, 2.00 eq) in dimethylsulfoxide (5.00 mL) was addedpotassium tert-butoxide (1.03 g, 9.16 mmol, 3.00 eq) in portions at 20°C. The mixture was stirred at 20° C. for 12 h. The reaction mixture wasadded water (200 mL) and filtered. The filter cake was dried to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)-6-nitroquinazolin-4-amine(1.40 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=10.06 (brs, 1H), 9.20 (s, 1H), 8.64-8.58 (m, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.89(td, J=7.6, 1.6 Hz, 1H), 7.70 (dd, J=9.0, 2.4 Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.46 (s, 1H), 7.38 (dd, J=7.0, 5.0 Hz, 1H), 7.29 (d, J=9.0 Hz,1H), 5.30 (s, 2H), 4.34 (br t, J=5.8 Hz, 2H), 3.01-2.92 (m, 1H), 2.24(s, 3H), 2.23-2.18 (m, 1H), 2.17-2.04 (m, 2H), 1.99-1.86 (m, 1H),1.77-1.44 (m, 4H). MS (ESI) m/z 535.3 [M+H]+

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)-6-nitroquinazolin-4-amine(1.40 g, 2.62 mmol, 1.00 eq) and ammonium chloride (1.26 g, 23.6 mmol,823 uL, 9.00 eq) in methanol (40.0 mL) and water (10.0 mL) was addediron powder (1.02 g, 18.3 mmol, 7.00 eq) in portions. The mixture wasstirred at 80° C. for 2 h. The mixture was added methanol (200 mL) andfiltered. The filtrate was concentrated to give crude product. The crudeproduct was purified by reverse-phase chromatography (FA-MeCN) andlyophilized to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)quinazoline-4,6-diamine(1.00 g, 1.98 mmol, 76% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.48 (br s, 1H), 8.62-8.57 (m, 1H), 8.38 (s, 1H), 8.15 (s,1H), 8.03 (d, J=2.6 Hz, 1H), 7.89 (td, J=7.8, 1.8 Hz, 1H), 7.69 (dd,J=9.0, 2.6 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.40-7.34 (m,1H), 7.24 (d, J=9.2 Hz, 1H), 7.13 (s, 1H), 5.48 (br s, 2H), 5.28 (s,2H), 4.34 (dt, J=10.2, 5.2 Hz, 1H), 4.26-4.18 (m, 1H), 3.59 (br s, 2H),3.07 (br s, 2H), 2.84 (s, 3H), 2.35-2.23 (m, 1H), 2.15 (br s, 1H),2.07-1.91 (m, 2H), 1.80 (br s, 1H). MS (ESI) m/z 505.3 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)quinazoline-4,6-diamine (300 mg, 594 umol, 1.00 eq), acrylic acid (64.2mg, 891 umol, 61.2 uL, 1.50 eq) and pyridine (141 mg, 1.78 mmol, 144 uL,3.00 eq) in dimethyl formamide (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (456 mg,2.38 mmol, 4.00 eq) in portions at 20° C. The mixture was stirred at 20°C. for 1 h. The mixture was filtered. The filtrate was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (10 mM NH4HCO3)-ACN]; B %: 40%-70%, 10 min) and lyophilized togive N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)quinazolin-6-yl)acrylamide95 (100.54 mg, 178 umol, 30% yield, 99% purity) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=9.01 (s, 1H), 8.56 (s, 1H), 8.53 (d, J=4.8 Hz,1H), 8.27 (s, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.72-7.66 (m, 1H), 7.64-7.58(m, 2H), 7.45 (dd, J=9.0, 2.6 Hz, 1H), 7.19-7.14 (m, 2H), 6.94 (d, J=9.0Hz, 1H), 6.47-6.39 (m, 1H), 6.32-6.22 (m, 1H), 5.80 (d, J=11.0 Hz, 1H),5.23 (s, 2H), 4.23 (t, J=6.4 Hz, 2H), 3.13-3.03 (m, 1H), 2.33 (s, 3H),2.31-2.10 (m, 4H), 2.04-1.95 (m, 1H), 1.94-1.81 (m, 2H), 1.59-1.52 (m,1H). MS (ESI) m/z 559.3 [M+H]+

96: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(800 mg, 1.88 mmol, 1.00 eq) and (S)-(1-methylpyrrolidin-2-yl)methanol(325 mg, 2.82 mmol, 339 uL, 1.50 eq) in dimethyl sulfoxide (15.0 mL) wasadded potassium tert-butoxide (632 mg, 5.64 mmol, 3.00 eq) in portionsat 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixturewas diluted with water (50 mL) and filtered. The filter cake was driedto give(S)—N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)methoxy)-6-nitroquinazolin-4-amine(800 mg, crude) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.74 (s,1H), 8.62 (br d, J=4.2 Hz, 1H), 8.53 (s, 1H), 7.88 (d, J=2.4 Hz, 1H),7.83-7.73 (m, 1H), 7.68 (br d, J=7.8 Hz, 1H), 7.54 (br s, 1H), 7.48 (dd,J=8.8, 2.6 Hz, 1H), 7.41 (s, 1H), 7.26 (brs, 1H), 7.05 (d, J=9.0 Hz,1H), 5.47-5.16 (m, 2H), 4.29-4.09 (m, 2H), 3.15 (br t, J=8.0 Hz, 1H),2.92-2.76 (m, 1H), 2.53 (s, 3H), 2.44-2.30 (m, 1H), 1.98-1.66 (m, 4H).

A mixture of(S)—N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)methoxy)-6-nitroquinazolin-4-amine(400 mg, 768 umol, 1.00 eq), iron powder (214 mg, 3.84 mmol, 5.00 eq),ammonium chloride (205 mg, 3.84 mmol, 134 uL, 5.00 eq) in methanol (20.0mL) and water (10.0 mL) was stirred at 80° C. for 1.5 h under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureto remove solvent. The residue was triturated with water (50 mL) andfiltered. The filter cake was washed with methanol. The filtrate wasconcentrated under reduced pressure to give(S)-N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)methoxy)quinazoline-4,6-diamine(200 mg, crude) as a yellow solid. MS (ESI) m/z 491.4 [M+H]+

To a solution of(S)-N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)methoxy)quinazoline-4,6-diamine (170 mg, 346 umol, 1.00 eq) and triethylamine(70.1 mg, 692 umol, 96.4 uL, 2.00 eq) in dimethyl formamide (4.00 mL)was added acrylic anhydride (56.8 mg, 450 umol, 1.30 eq) dropwise at 25°C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC (column: Xtimate C18150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN];B %: 37%-67%, 10 min) to give(S)—N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-6-yl)acrylamide96 (124.49 mg, 228 umol, 65% yield, 100% purity, 99% ee) as a yellowsolid. 1H NMR (400 MHz, CDCl3) δ=9.11 (s, 1H), 8.86 (br s, 1H), 8.65 (s,1H), 8.62 (d, J=5.0 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.82-7.74 (m, 1H),7.71-7.65 (m, 1H), 7.58 (s, 1H), 7.52 (dd, J=8.8, 2.6 Hz, 1H), 7.31 (s,1H), 7.26 (br d, J=6.8 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.56-6.45 (m,1H), 6.44-6.31 (m, 1H), 5.86 (d, J=11.2 Hz, 1H), 5.32 (s, 2H), 4.50-4.39(m, 2H), 3.19 (br d, J=7.4 Hz, 1H),2.79 (brs, 1H), 2.51 (s, 3H),2.46-2.36 (m, 1H), 2.16-2.02 (m, 1H), 1.98-1.92 (m, 3H). MS (ESI) m/z545.4 [M+H]+

97: A mixture of 2,3-dichloro-5-nitropyridine (1.50 g, 7.77 mmol, 1.00eq), pyridin-2-ylmethanamine (1.01 g, 9.33 mmol, 951 uL, 1.20 eq) inacetonitrile (30.0 mL) was stirred at 25° C. for 4 h under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureto give a residue. The residue was purified by flash silica gelchromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of0˜1% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give3-chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-2-amine (1.50 g, 5.67mmol, 73% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.87 (d,J=2.2 Hz, 1H), 8.52 (br d, J=4.8 Hz, 2H), 8.43 (d, J=2.4 Hz, 1H), 7.74(td, J=7.6, 1.6 Hz, 1H), 7.40-7.14 (m, 2H), 4.82 (d, J=6.0 Hz, 2H).

A mixture of 3-chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-2-amine(1.20 g, 4.53 mmol, 1.00 eq), iron powder (1.27 g, 22.7 mmol, 5.00 eq)and ammonium chloride (1.21 g, 22.7 mmol, 793 uL, 5.00 eq) in methanol(10.0 mL) and water (5.00 mL) was stirred at 80° C. for 2 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure to remove solvent to give a residue. The residue was purifiedby flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica FlashColumn, Eluent of 40-100% Ethyl acetate/Petroleum ether gradient @ 50mL/min) to give 3-chloro-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine(500 mg, 2.13 mmol, 47% yield) as an off-white solid. 1H NMR (400 MHz,DMSO-d6) δ=8.50 (d, J=4.2 Hz, 1H), 7.70 (td, J=7.8, 1.8 Hz, 1H), 7.43(d, J=2.4 Hz, 1H), 7.32-7.18 (m, 2H), 7.05 (d, J=2.4 Hz, 1H), 6.22 (t,J=5.8 Hz, 1H), 4.59 (br s, 2H), 4.55 (d, J=5.8 Hz, 2H).

A mixture of 4-chloro-7-fluoro-6-nitroquinazoline (400 mg, 1.76 mmol,1.00 eq), 3-chloro-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine (495 mg,2.11 mmol, 1.20 eq) in isopropanol (30.0 mL) was stirred at 80° C. for 2h under nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure to remove solvent to give3-chloro-N5-(7-fluoro-6-nitroquinazolin-4-yl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine(750 mg, crude) as a yellow solid. MS (ESI) m/z 426.0 [M+H]+

To a solution of 2-morpholinoethanol (555 mg, 4.23 mmol, 518 uL, 3.00eq) in tetrahydrofuran (15.0 mL) was added sodium hydrogen (338 mg, 8.45mmol, 60% purity, 6.00 eq) at 0° C. and the mixture was stirred for 0.5h. Then The mixture was added3-chloro-N5-(7-fluoro-6-nitroquinazolin-4-yl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine(600 mg, 1.41 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) dropwise at 0°C. The mixture was stirred at 0° C. for 2 h. The reaction mixture wasquenched by water (5.0 mL) at 0° C., then diluted with water (40 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine (3×20 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give3-chloro-N5-(7-(2-morpholinoethoxy)-6-nitroquinazolin-4-yl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine(750 mg, crude) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.84 (s,1H), 8.78-8.70 (m, 1H), 8.68-8.64 (m, 1H), 8.56 (br d, J=4.4 Hz, 1H),8.08 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.72-7.66 (m, 1H),7.38-7.32 (m, 2H), 7.24-7.18 (m, 1H), 6.22 (br t, J=5.2 Hz, 1H),4.89-4.77 (m, 1H), 4.89-4.77 (m, 1H), 4.36 (t, J=5.4 Hz, 2H), 3.78-3.72(m, 4H), 2.99-2.85 (m, 2H), 2.70-2.59 (m, 4H).

A mixture of3-chloro-N5-(7-(2-morpholinoethoxy)-6-nitroquinazolin-4-yl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-diamine(400 mg, 745 umol, 1.00 eq), iron powder (208 mg, 3.72 mmol, 5.00 eq),ammonium chloride (199 mg, 3.72 mmol, 130 uL, 5.00 eq) in methanol (20.0mL) and water (5.00 mL) was stirred at 80° C. for 2 h under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureto remove solvent. The residue was triturated with water (50 mL) andfiltered. The filter cake was dissolved in methanol (100 mL) andfiltered. The filtrate was concentrated under reduced pressure to giveN4-(5-chloro-6-((pyridin-2-ylmethyl)amino)pyridin-3-yl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine(200 mg, crude) as a brown solid. MS (ESI) m/z 507.4 [M+H]+

To a solution ofN4-(5-chloro-6-((pyridin-2-ylmethyl)amino)pyridin-3-yl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine (200 mg, 395 umol, 1.00 eq) and triethylamine(79.8 mg, 789 umol, 109 uL, 2.00 eq) in dimethyl formamide (3.00 mL) wasadded acrylic anhydride (64.7 mg, 512 umol, 1.30 eq) dropwise at 25° C.Then the mixture was stirred at 25° C. for 0.5 h. The reaction mixturewas filtered. The filtrate was purified by prep-HPLC (column: XtimateC18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 27%-57%, 10 min) and lyophilized to giveN-(4-((5-chloro-6-((pyridin-2-ylmethyl)amino)pyridin-3-yl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)acrylamide97 (49.00 mg, 82.1 umol, 21% yield, 94% purity) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ=9.11 (s, 1H), 8.84 (s, 1H), 8.62 (br d, J=4.2 Hz,1H), 8.59 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.83(s, 1H), 7.68 (td, J=7.8, 1.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26 (s,1H), 7.22 (dd, J=6.8, 5.2 Hz, 1H), 6.59-6.35 (m, 2H), 6.23 (t, J=5.0 Hz,1H), 6.07-5.79 (m, 1H), 4.82 (d, J=5.2 Hz, 2H), 4.35 (t, J=5.4 Hz, 2H),3.84-3.72 (m, 4H), 2.93 (t, J=5.4 Hz, 2H), 2.65-2.54 (m, 4H). MS (ESI)m/z 561.4 [M+H]+

98: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(2.00 g, 4.70 mmol, 1.00 eq), cyclopropane-1,1-diyldimethanol (959 mg,9.39 mmol, 2.00 eq) and potassium tert-butoxide (2.11 g, 18.8 mmol, 4.00eq) in dimethylsulfoxide (20.0 mL) was stirred at 25° C. for 1 h. To themixture was added water (20.0 mL). The mixture was filtered. The filtercake was dried to give(1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)cyclopropyl)methanol(2.10 g, 4.13 mmol, 88% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.07 (br s, 1H), 9.21 (s, 1H), 8.61 (br s, 2H), 8.08-7.97(m, 1H), 7.89 (br t, J=7.3 Hz, 1H), 7.70 (br d, J=8.7 Hz, 1H), 7.59 (brd, J=7.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.29 (br d, J=8.9 Hz, 1H), 5.30 (s,2H), 4.78-4.57 (m, 1H), 4.21 (s, 2H), 3.44 (br d, J=5.0 Hz, 2H), 0.57(br d, J=3.4 Hz, 4H). MS (ESI) m/z 508.0 [M+H]+

The mixture of(1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)cyclopropyl)methanol (2.00 g, 3.94 mmol, 1.00 eq) and sulfurousdichloride (3.28 g, 27.6 mmol, 2.00 mL, 7.00 eq) in tetrahydrofuran(20.0 mL) and dichloromethane (20.0 mL) was stirred at 50° C. for 2 h.The reaction mixture was concentrated to give a residue. The residue wastriturated with ethyl acetate (20.0 mL) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(chloromethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine(2.00 g, 3.80 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.61 (s, 1H), 8.92 (s, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.10-8.05(m, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.67 (br dd,J=2.5, 8.9 Hz, 1H), 7.62 (s, 1H), 7.55 (dd, J=5.4, 7.0 Hz, 1H), 7.38 (d,J=9.2 Hz, 1H), 5.42 (s, 2H), 4.31 (s, 2H), 3.86-3.64 (m, 2H), 0.94-0.76(m, 4H). MS (ESI) m/z 526.0 [M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-(chloromethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine(1.00 g, 1.90 mmol, 1.00 eq), dimethylamine (171 mg, 3.80 mmol, 2.00eq), potassium carbonate (1.05 g, 7.60 mmol, 4.00 eq) and potassiumiodide (315 mg, 1.90 mmol, 1.00 eq) in acetonitrile (20.0 mL) wasstirred at 110° C. for 12 h. The reaction mixture was concentrated togive a residue. The residue was triturated with water (20.0 mL) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine(950 mg, 1.78 mmol, 93% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.04 (s, 1H), 8.53 (br d, J=4.3 Hz, 1H), 8.40 (s, 1H), 7.86(d, J=2.2 Hz, 1H), 7.83-7.79 (m, 1H), 7.52 (br d, J=7.6 Hz, 2H), 7.29(br d, J=7.0 Hz, 1H), 7.22 (s, 1H), 7.16 (br d, J=8.9 Hz, 1H), 5.21 (s,2H), 4.07 (s, 2H), 2.18 (s, 2H), 2.09 (s, 6H), 0.58 (s, 2H), 0.42-0.31(m, 2H). MS (ESI) m/z 535.2 [M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-amine (800 mg, 1.50 mmol, 1.00 eq), iron(417 mg, 7.48 mmol, 5.00 eq) and ammonium chloride (399 mg, 7.48 mmol,5.00 eq) in methanol (10.0 mL) and water (10.0 mL) was stirred at 80° C.for 2 h. To the mixture was added methanol (40.0 mL). The mixture wasfiltered. The filtrate was concentrated to give a residue. The residuewas triturated with saturated sodium carbonate (20.0 mL) to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)quinazoline-4,6-diamine (600 mg, crude) as a yellow solid. MS (ESI) m/z505.2 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)quinazoline-4,6-diamine (300 mg, 594 umol, 1.00 eq), pyridine(188 mg, 2.38 mmol, 4.00 eq) and acrylic acid (51.4 mg, 713 umol, 1.20eq) in dimethyl formamide (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (455 mg, 2.38 mmol, 4.00eq) at 25° C. The mixture was stirred at 25° C. for 0.5 h. The reactionmixture was filtered. The filtrate was purified by prep-HPLC {column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−ACN]; B %: 43/6-73%, 10 min} and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)quinazolin-6-yl)acrylamide98 (82.51 mg, 144 umol, 24% yield, 98% purity) as a green solid. 1H NMR(400 MHz, DMSO-d6) δ=9.67 (s, 1H), 9.52 (s, 1H), 8.77 (s, 1H), 8.67-8.56(m, 1H), 8.50 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.8, 7.7 Hz,1H), 7.71 (dd, J=2.6, 9.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.38 (dd,J=5.4, 7.0 Hz, 1H), 7.31-7.21 (m, 2H), 6.66 (br dd, J=10.3, 16.9 Hz,1H), 6.32 (dd, J=2.0, 17.0 Hz, 1H), 5.83 (dd, J=1.9, 10.2 Hz, 1H), 5.29(s, 2H), 4.10 (s, 2H), 2.29 (s, 2H), 2.18 (s, 6H), 0.74-0.62 (m, 2H),0.52-0.36 (m, 2H). MS (ESI) m/z 559.4 [M+H]+

99: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.30 g, 3.05 mmol, 1.00 eq) and 1-methylazepan-4-ol (789 mg, 6.11 mmol,2.00 eq) in dimethylsulfoxide (10.0 mL) was added potassiumtert-butoxide (1.03 g, 9.16 mmol, 3.00 eq) in portions at 20° C. Themixture was stirred at 20° C. for 12 h. The reaction mixture was addedwater (50 mL) and filtered. The filter cake was dried to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazepan-4-yl)oxy)-6-nitroquinazolin-4-amine(1.60 g, crude) as a yellow solid. MS (ESI) m/z 535.3 [M+H]+

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((I-methylazepan-4-yl)oxy)-6-nitroquinazolin-4-amine(1.60 g, 2.99 mmol, 1.00 eq) and ammonium chloride (1.44 g, 26.9 mmol,941 uL, 9.00 eq) in methanol (40.0 mL) and water (10.0 mL) was addediron powder (1.17 g, 20.9 mmol, 7.00 eq) in portions. The mixture wasstirred at 80° C. for 2 h. The mixture was added methanol (50 mL) andfiltered. The filtrate was concentrated to give the residue. The residuewas purified by prep-HPLC (column: Kromasil 250*50 mm*10 um; mobilephase: [water (0.1% TFA)-ACN]; B %: 12ACN %-42ACN %, 25 min, 45% min)and lyophilized to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazepan-4-yl)oxy)quinazoline-4,6-diamine (350 mg, 693 umol, 23% yield) as a yellowsolid. 1H NMR (400 MHz, MeOD) δ=8.71 (br s, 1H), 8.57 (s, 1H), 8.28-8.14(m, 1H), 7.98-7.90 (m, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.73-7.58 (m, 2H),7.52 (s, 1H), 7.29-7.23 (m, 2H), 5.42 (s, 2H), 5.10 (br s, 1H),3.79-3.59 (m, 2H), 3.56-3.44 (m, 1H), 3.25 (br d, J=7.1 Hz, 1H), 2.99(s, 3H), 2.53-2.37 (m, 2H), 2.35-2.08 (m, 3H), 1.98 (br s, 1H). MS (ESI)m/z 505.4 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazepan-4-yl)oxy)quinazoline-4,6-diamine(300 mg, 594 umol, 1.00 eq) and triethylamine (180 mg, 1.78 mmol, 248uL, 3.00 eq) in dimethyl formamide (3.00 mL) was added acrylic anhydride(97.4 mg, 772 umol, 1.30 eq) dropwise at 20° C. The mixture was stirredat 20° C. for 1 h. The mixture was filtered and the filtrate waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um;mobile phase: [water (0.225% FA)-ACN]; B %: 5%-35%, 10 min) andlyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylazepan-4-yl)oxy)quinazolin-6-yl)acrylamide99 (17.34 mg, 28.4 umol, 5% yield, 99% purity, FA) as a yellow solid. 1HNMR (400M Hz, MeOD) δ=8.79 (s, 1H), 8.58 (br d, J=4.2 Hz, 2H), 8.45 (s,1H), 7.97-7.87 (m, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.58 (dd, J=8.8, 2.6 Hz,1H), 7.41 (dd, J=6.8, 5.2 Hz, 1H), 7.19 (s, 1H), 7.16 (d, J=9.0 Hz, 1H),6.72-6.62 (m, 1H), 6.53-6.43 (m, 1H), 5.95-5.85 (m, 1H), 5.28 (s, 2H),5.04-4.96 (m, 1H), 3.28-3.20 (m, 1H), 3.17-2.96 (m, 3H), 2.69 (s, 3H),2.45-2.34 (m, 1H), 2.33-2.21 (m, 2H), 2.19-2.11 (m, 1H), 2.09-1.98 (m,1H), 1.92-1.79 (m, 1H). MS (ESI) m/z 559.3 [M+H]+

100: To a solution of tert-butyl nitrite (10.0 g, 79.3 mmol, 11.5 mL,1.00 eq) in acetonitrile (100 mL) was added 5-fluoro-2-methylphenol(9.81 g, 95.1 mmol, 1.20 eq) at 25° C. The mixture was stirred at 25° C.for 12 h. The mixture was quenched with 5% aqueous solution of sodiumthiosulfate (50.0 mL) and extracted with ethyl acetate (200 mL). Theorganic layer was washed with water (200 mL), dried over sodium sulfate,filtered and the filtrate was concentrated to afford a residue. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=1/0 to 3/1) to give 5-fluoro-2-methyl-4-nitrophenol (4.00 g,crude) as a brown solid. 1H NMR (400 MHz, CDCl3) δ=7.94 (d, J=8.4 Hz,1H), 6.66 (d, J=11.6 Hz, 1H), 5.63 (s, 1H), 2.27 (s, 3H).

A mixture of 5-fluoro-2-methyl-4-nitrophenol (4.00 g, 23.4 mmol, 1.00eq), 2-(chloromethyl)pyridine (7.67 g, 46.8 mmol, 2.00 eq, HCl) andpotassium carbonate (25.8 g, 187 mmol, 8.00 eq) in acetonitrile (100 mL)was stirred at 90° C. for 1 h. The reaction was filtered and the filtercake was washed with ethyl acetate (100 mL). The filtrate wasconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0 to 3/1) to give2-((5-fluoro-2-methyl-4-nitrophenoxy) methyl)pyridine (1.20 g, 4.58mmol, 20% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.67-8.60(m, 1H), 7.95 (dd, J=0.7, 8.4 Hz, 1H), 7.76 (dt, J=1.8, 7.7 Hz, 1H),7.47 (d, J=7.8 Hz, 1H), 7.31-7.27 (m, 1H), 6.76 (d, J=12.7 Hz, 1H), 5.27(s, 2H), 2.32 (s, 3H).

To a solution of 2-((5-fluoro-2-methyl-4-nitrophenoxy)methyl)pyridine(1.10 g, 4.19 mmol, 1.00 eq) in ethanol (10.0 mL) was added water (3.00mL), ammonium chloride (1.12 g, 21.0 mmol, 5.00 eq) and iron powder (703mg, 12.6 mmol, 3.00 eq). The reaction mixture was stirred at 80° C. for1 h. The reaction mixture was filtered. The filtrate was concentrated invacuo. To the residue was added water (30.0 mL) and extracted with ethylacetate (3×50.0 mL). The combined organic layer was washed with brine(30.0 mL), dried over sodium sulfate, filtered and concentrated in vacuoto give 2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)aniline (900 mg, 3.88mmol, 92% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ=8.57 (dd,J=0.8, 4.0 Hz, 1H), 7.86-7.79 (m, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.37-7.27(m, 1H), 6.77 (d, J=12.8 Hz, 1H), 6.61 (d, J=10.3 Hz, 1H), 5.04 (s, 2H),4.56 (s, 2H), 2.10 (s, 3H).

To a solution of 4-chloro-7-fluoro-6-nitroquinazoline (490 mg, 2.15mmol, 1.00 eq) in isopropanol (10.0 mL) was added2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)aniline (500 mg, 2.15 mmol,1.00 eq). The reaction mixture was stirred at 90° C. for 1 h. Thereaction mixture was concentrated in vacuo to give7-fluoro-N-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(600 mg, crude) as a yellow solid. MS (ESI) m/z 424.3 [M+H]+

To a solution of 2-morpholinoethanol (310 mg, 2.36 mmol, 2.00 eq) intetrahydrofuran (0.500 mL) was added sodium hydride (189 mg, 4.72 mmol,60% purity, 4.00 eq). The reaction mixture was stirred at 0° C. for 0.5h. Then7-fluoro-N-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(500 mg, 1.18 mmol, 1.00 eq) was added. The reaction mixture was stirredat 0° C. for 1 h. The reaction mixture was quenched with water (10.0mL), extracted with ethyl acetate (3×10.0 mL). The combined organiclayer was washed with brine (3-10 mL), dried over sodium sulfate,filtered and concentrated to giveN-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)-6-nitroquinazolin-4-amine(200 mg, 374 umol, 32% yield) as a pink oil. 1H NMR (400 MHz, DMSO)δ=10.00 (s, 1H), 9.15 (s, 1H), 8.63-8.57 (m, 1H), 8.49 (s, 1H), 7.89(dt, J=1.8, 7.7 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.50 (s, 1H), 7.38 (dt,J=0.9, 6.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.08 (d, J=12.1 Hz, 1H),5.26 (s, 2H), 4.43 (t, J=5.5 Hz, 2H), 3.62-3.51 (m, 4H), 3.31 (br s,4H), 2.78 (t, J=5.5 Hz, 2H), 2.24 (s, 3H). MS (ESI) m/z 535.4 [M+H]+

To a solution ofN-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)-6-nitroquinazolin-4-amine(160 mg, 299 umol, 1.00 eq) in ethanol (6.00 mL) was added water (3.00mL), iron powder (50.2 mg, 898 umol, 3.00 eq) and ammonium chloride(80.1 mg, 1.50 mmol, 5.00 eq). The reaction mixture was stirred at 80°C. for 1 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was dissolved in water (10.0 mL),extracted with ethyl acetate (2×10 mL). The combined organic layer waswashed with brine (3×10 mL), dried over sodium sulfate, filtered andconcentrated to giveN4-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine (130 mg, 258 umol, 86% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ=8.61 (br d, J=4.4 Hz, 1H), 8.55 (s, 1H), 8.07(d, J=9.2 Hz, 1H), 7.74 (dt, J=1.6, 7.7 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H),7.26-7.20 (m, 1H), 7.17 (s, 1H), 7.01 (br s, 1H), 6.95 (s, 1H), 6.73 (d,J=12.3 Hz, 1H), 5.19 (s, 2H), 4.48-4.18 (m, 4H), 3.80-3.68 (m, 4H), 2.90(t, J=5.6 Hz, 2H), 2.66-2.55 (m, 4H), 2.34 (s, 3H).

To a solution ofN4-(2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine (100 mg, 198 umol, 1.00 eq) in dimethylformamide(0.500 mL) was added acrylic acid (0.500 M solution indimethylformamide, 595 uL, 1.50 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.0 mg,297 umol, 1.50 eq) and pyridine (47.0 mg, 595 umol, 3.00 eq). Thereaction mixture was stirred at 20° C. for 1 h. The reaction mixture wasfiltered. The filtrate was purified by Prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:6%-30%, 8 min) and lyophilized to giveN-(4-((2-fluoro-5-methyl-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)acrylamide100 (68.86 mg, 123.27 umol, 62% yield, 100% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ=9.61 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H),8.61 (dd, J=0.7, 4.8 Hz, 1H), 8.33 (s, 1H), 7.89 (dt, J=1.8, 7.7 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.29 (s, 1H), 7.23 (d,J=8.8 Hz, 1H), 7.04 (d, J=12.2 Hz, 1H), 6.69 (dd, J=10.1, 17.0 Hz, 1H),6.30 (dd, J=1.8, 17.0 Hz, 1H), 5.86-5.72 (m, 1H), 5.24 (s, 2H), 4.34 (t,J=5.7 Hz, 2H), 3.61-3.52 (m, 4H), 2.83 (t, J=5.7 Hz, 2H), 2.54-2.51 (m,4H), 2.23 (s, 3H). MS (ESI) m/z 559.4 [M+H]+.

101: To a solution of 1-methylpyrrolidine-3-carboxylic acid (1.00 g,6.04 mmol, 1.00 eq, hydrochloride) in tetrahydrofuran (10.0 mL) wasadded borane dimethyl sulfide complex (10.0 M, 15.1 mmol, 2.50 eq) at 0°C. The mixture was stirred at 20° C. for 12 h. Saturated sodiumbicarbonate (5.00 mL) was added and the resulting mixture was stirredfor 0.5 h. The mixture was extracted with ethyl acetate (3×20.0 mL). Theorganic was washed with brine (3×20.0 mL), and dried over anhydroussodium sulfate, filtered and concentrated to give(1-methylpyrrolidin-3-yl)methanol (0.600 g, crude) as yellow oil. 1H NMR(400 MHz, DMSO-d6) δ=4.71 (t, J=5.1 Hz, 1H), 3.44-3.33 (m, 2H),3.15-3.06 (m, 1H), 3.04-2.94 (m, 1H), 2.83-2.73 (m, 1H), 2.59 (s, 3H),2.57-2.52 (m, 2H), 2.11-2.00 (m, 1H), 1.67-1.60 (m, 1H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.06 g, 2.48 mmol, 1.00 eq), (1-methylpyrrolidin-3-yl)methanol (0.400g, 3.47 mmol, 1.40 eq) in dimethylsulfoxide (13.0 mL) was addedpotassium tert-butoxide (835 mg, 7.44 mmol, 3.00 eq). The mixture wasstirred at 20° C. for 12 h. The mixture was added ice-water (30.0 mL)and stirred for 0.5 h. After filtration, the filter cake was trituratedwith petroleum ether (5.00 mL) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)methoxy)-6-nitroquinazolin-4-amine(1.00 g, 1.92 mmol, 77% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.10 (s, 1H), 9.29-9.22 (m, 1H), 8.64 (s, 1H), 8.61 (br d,J=4.6 Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.5, 7.7 Hz, 11H),7.71 (dd, J=2.5, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.50-7.45 (m, 1H),7.41-7.35 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 5.31 (s, 2H), 4.40-4.28 (m,2H), 3.14-3.06 (m, 1H), 2.96 (br s, 1H), 2.93-2.85 (m, 1H), 2.80-2.73(m, 1H), 2.67 (s, 3H), 2.31-2.23 (m, 1H), 1.85 (br dd, J=8.2, 13.3 Hz,1H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)methoxy)-6-nitroquinazolin-4-amine(0.800 g, 1.54 mmol, 1.00 eq) in methanol (40.0 mL) were added ammoniumchloride (411 mg, 7.68 mmol, 5.00 eq), iron powder (429 mg, 7.68 mmol,5.00 eq) and water (10.0 mL). The mixture was stirred at 80° C. for 12h. The mixture was added methanol (50.0 mL) and stirred at 55° C. for0.5 h, then filtered. The filtrate was concentrated to afford a residue.The residue was diluted with saturated sodium bicarbonate (5.00 mL),extracted with dichloromethane/methanol (10/1, 2×20.0 mL). The organiclayer was washed with water (3×20.0 mL), dried over anhydrous sodiumsulfate, filtered and concentrated to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)methoxy)quinazoline-4,6-diamine (0.600 g, 1.22 mmol, 79% yield) as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) δ=9.24 (s, 1H), 8.60 (dd, J=0.9, 4.0Hz, 1H), 8.37-8.29 (m, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.8, 7.7Hz, 1H), 7.70 (dd, J=2.6, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.38 (s,1H), 7.38-7.35 (m, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.07 (s, 1H), 5.27 (s,4H), 4.10-4.00 (m, 2H), 2.70-2.62 (m, 2H), 2.56-2.54 (m, 1H), 2.47-2.38(m, 2H), 2.26 (s, 3H), 2.08-1.96 (m, 1H), 1.63-1.53 (m, 1H). MS (ESI)m/z 491.3, [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-3-yl)methoxy)quinazoline-4,6-diamine (0.300 g, 611 umol, 1.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (234 mg,1.22 mmol, 2.00 eq) and pyridine (145 mg, 1.83 mmol, 3.00 eq) inN,N-dimethylformamide (1.00 mL) was added acrylic acid (0.500 M, 1.59mL, 794 mmol, 1.30 eq). The mixture was stirred at 20° C. for 1 h. Themixture was filtered and the filtrate was purified by prep-HPLC (column:Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-acetonitrile]; B %: 52%-82%, 10 min) to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylpyrrolidin-3-yl)methoxy)quinazolin-6-yl)acrylamide101 (150 mg, 276 umol, 45% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.68 (s, 1H), 9.54 (s, 1H), 8.84 (s, 1H), 8.60 (d, J=4.2 Hz,1H), 8.49 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.88 (dt, J=1.7, 7.7 Hz, 1H),7.69 (dd, J=2.6, 8.9 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1,6.8 Hz, 1H), 7.28-7.22 (m, 2H), 6.67 (dd, J=10.3, 17.0 Hz, 1H), 6.32(dd, J=1.8, 17.0 Hz, 1H), 5.83 (dd, J=1.8, 10.2 Hz, 1H), 5.29 (s, 2H),4.16-4.05 (m, 2H), 2.71-2.63 (m, 1H), 2.60-2.53 (m, 2H), 2.45-2.35 (m,2H), 2.25 (s, 3H), 2.03-1.91 (m, 1H), 1.59 (dt, J=7.0, 12.7 Hz, 1H). MS(ESI) m/z 545.4, [M+H]+

102: A mixture of 3-hydroxypropanenitrile (10.0 g, 141 mmol, 9.52 mL,1.00 eq), (bromomethyl)benzene (24.1 g, 141 mmol, 16.7 mL, 1.00 eq) andN,N-diisopropylethylamine (21.8 g, 169 mmol, 29.4 mL, 1.20 eq) washeated to 150° C. and stirred at 150° C. for 2 h. The mixture was cooledto room temperature and diluted with sulfuric acid (1 M, 100 mL) andethyl acetate (100 mL). The organic layer was washed with water (100mL), dried over sodium sulfate, filtered and the filtrate wasconcentrated to afford a brown oil. The brown oil was distilled undervacuum (˜5 torr) and collected the distillate between 140 to 150° C. togive 3-(benzyloxy)propanenitrile (10.0 g, 62.0 mmol, 44% yield) ascolorless oil. 1H NMR (400 MHz, CDCl3) δ=7.43-7.28 (m, 5H), 4.58 (s,2H), 3.68 (t, J=6.4 Hz, 2H), 2.62 (t, J=6.4 Hz, 2H).

To a solution of 3-(benzyloxy)propanenitrile (9.00 g, 55.8 mmol, 1.00eq) in dry tetrahydrofuran (180 mL) was added tetraisopropoxytitanium(17.5 g, 61.4 mmol, 18.1 mL, 1.10 eq) and ethylmagnesium bromide (3 M,37.2 mL, 2.00 eq) in turn at 20° C. The mixture was stirred at 20° C.for 0.5 h before a mixture of boron trifluoride in diethyl ether (15.9g, 112 mmol, 13.8 mL, 2.00 eq) was added in one portion. The mixture wasadded water (100 mL) and adjusted pH>with sodium hydroxide. The mixturewas extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water (2×100 mL) and then added hydrochloric acid (1 M,200 mL) in water. After separation, the aqueous phase was washed withethyl acetate (2×100 mL) and then basified with sodium hydroxide topH>10. The product was extracted with ethyl acetate (2-100 mL) and thecombined organic phase was washed with water (100 mL), dried over sodiumsulfate, filtered and concentrated to afford1-(2-(benzyloxy)ethyl)cyclopropanamine (4.40 g, 23.0 mmol, 41% yield) ascolorless oil. 1H NMR (400 MHz, CDCl3) δ=7.37-7.30 (m, 5H), 4.53 (s,2H), 3.68 (t, J=6.3 Hz, 2H), 1.73 (t, J=6.3 Hz, 2H), 0.59-0.52 (m, 2H),0.46-0.40 (m, 2H).

To a solution of 1-(2-(benzyloxy)ethyl)cyclopropanamine (4.40 g, 23.0mmol, 1.00 eq) in acetonitrile (50.0 mL) was added formaldehyde (37%,7.47 g, 92.0 mmol, 6.85 mL, 4.00 eq) and sodium triacetoxyhydroborate(29.3 g, 138 mmol, 6.00 eq). The reaction mixture was stirred at 20° C.for 12 h. The reaction mixture was concentrated in vacuo. The residuewas added sat. sodium bicarbonate (100 mL) and extracted with ethylacetate (3×100 mL). The organic layer was washed with water (100 mL),dried over sodium sulfate, filtered and concentrated in vacuo to give1-(2-(benzyloxy)ethyl)-N,N-dimethylcyclopropanamine (3.50 g, 16.0 mmol,69% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ=7.10-7.03 (m,5H), 4.18 (s, 2H), 3.18 (t, J=7.1 Hz, 2H), 1.96 (s, 6H), 1.56-1.50 (m,2H), 0.23-0.15 (m, 4H). MS (ESI) m/z 220.4[M+H]+.

To a solution of 1-(2-(benzyloxy)ethyl)-N,N-dimethylcyclopropanamine(1.50 g, 6.84 mmol, 1.00 eq) in methanol (20.0 mL) was addedhydrochloric acid (12 M, 2.28 mL, 4.00 eq) and palladium on carbon (150mg, 10% purity). The reaction mixture was stirred at 20° C. for 12 hunder hydrogen atmosphere (15 psi). The reaction mixture was filteredand concentrated in vacuo to give 2-(1-(dimethylamino)cyclopropyl)ethanol (800 mg, 4.83 mmol, 71% yield, HCl) as yellow oil. 1H NMR (400MHz, CD30D) δ=3.65 (t, J=5.9 Hz, 2H), 2.97-2.86 (m, 6H), 2.07 (t, J=5.9Hz, 2H), 1.22-1.16 (m, 2H), 1.09-1.04 (m, 2H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.00 g, 2.35 mmol, 1.00 eq) in dimethylsulfoxide (20.0 mL) was added2-(1-(dimethylamino)cyclopropyl)ethanol (778 mg, 4.70 mmol, 2.00 eq,HCl) and potassium tert-butoxide (791 mg, 7.05 mmol, 3.00 eq). Thereaction mixture was stirred at 20° C. for 12 h. The reaction mixturewas added water (30 mL) and filtered. The filter cake was dried in vacuoto giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-(dimethylamino)cyclopropyl)ethoxy)-6-nitroquinazolin-4-amine(1.20 g, 2.24 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, DMSO)δ=10.02 (br s, 1H), 9.16 (s, 1H), 8.63-8.54 (m, 2H), 7.99 (br d, J=2.1Hz, 1H), 7.92-7.81 (m, 1H), 7.67 (br d, J=8.8 Hz, 1H), 7.58 (br d, J=7.7Hz, 1H), 7.42 (br s, 1H), 7.39-7.33 (m, 1H), 7.27 (br d, J=8.9 Hz, 1H),5.29 (s, 2H), 4.28 (br d, J=5.9 Hz, 2H), 2.26 (s, 6H), 2.00 (br t, J=6.4Hz, 2H), 0.59-0.53 (m, 2H), 0.52-0.44 (m, 2H).

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-(dimethylamino)cyclopropyl)ethoxy)-6-nitroquinazolin-4-amine (1.10 g, 2.06 mmol, 1.00eq) in ethanol (20.0 mL) was added water (10.0 mL), ammonium chloride(550 mg, 10.3 mmol, 5.00 eq) and iron powder (344 mg, 6.17 mmol, 3.00eq). The reaction mixture was stirred at 80° C. for 2 h. The reactionmixture was filtered and concentrated in vacuo. To the residue was addedwater (50 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with brine (50 mL), dried over sodium sulfate,filtered and concentrated in vacuo to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-(dimethylamino)cyclopropyl)ethoxy)quinazoline-4,6-diamine (700 mg, 1.39 mmol, 67% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ=8.52 (br d, J=4.8 Hz, 1H), 8.47 (s, 1H), 7.76(d, J=2.3 Hz, 1H), 7.71-7.63 (m, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.39 (dd,J=2.4, 8.7 Hz, 1H), 7.16 (br d, J=6.1 Hz, 1H), 7.08 (s, 1H), 6.92 (d,J=9.0 Hz, 2H), 6.85 (s, 1H), 5.21 (s, 2H), 4.18 (br s, 2H), 4.11 (t,J=7.2 Hz, 2H), 2.31 (s, 6H), 2.05 (t, J=7.1 Hz, 2H), 0.64-0.59 (m, 2H),0.51-0.44 (m, 2H). MS (ESI) m/z 505.4 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(1-(dimethylamino)cyclopropyl)ethoxy)quinazoline-4,6-diamine (200 mg, 396 umol, 1.00 eq) in dimethyformamide(4.00 mL) was added acrylic acid (0.5 M in dimethyformamide, 1.19 mL,1.50 eq), pyridine (94.0 mg, 1.19 mmol, 3.00 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg, 594umol, 1.50 eq). The reaction mixture was stirred at 20° C. for 30 min.The reaction mixture was filtered. The filtrate was purified byprep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase:[water (0.225% FA)-ACN]; B %: 8%-35%, 10 min) and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(1-(dimethylamino)cyclopropyl)ethoxy)quinazolin-6-yl)acrylamide102 (98.87 mg, 133 umol, 34% yield, 100% purity, 4 FA) as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ=9.67 (br s, 1H), 9.56 (s, 1H), 8.83 (s, 1H),8.64-8.57 (m, 1H), 8.49 (s, 1H), 8.17 (s, 4H), 7.98 (d, J=2.6 Hz, 1H),7.88 (dt, J=1.7, 7.7 Hz, 1H), 7.69 (dd, J=2.5, 9.0 Hz, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.37 (dd, J=5.3, 7.1 Hz, 1H), 7.29-7.21 (m, 2H), 6.69(dd, J=10.2, 16.9 Hz, 1H), 6.32 (dd, J=1.9, 16.9 Hz, 1H), 5.85-5.75 (m,1H), 5.28 (s, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.30 (s, 6H), 2.08 (t, J=6.9Hz, 2H), 0.63-0.47 (m, 4H). MS (ESI) m/z 559.3 [M+H]+.

103: To a solution of tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.50 g, 20.0 mmol,1.00 eq) and methoxymethyl(triphenyl)phosphonium; chloride (13.7 g, 40.0mmol, 2.00 eq) in tetrahydrofuran (100 mL) was added potassiumtert-butoxide (4.48 g, 40.0 mmol, 2.00 eq) at 0° C. The mixture wasallowed to warm to 25° C. and stirred at 25° C. for 12 h. The mixturewas diluted with water (100 mL), extracted with ethyl acetate (2×200mL). The combined organic layers were washed with water, dried overanhydrous sodium sulfate, filtered and the filtrate was concentrated toafford a residue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=1/0-3/1) to afford tert-butyl5-(methoxymethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5.00 g, 17.4 mmol, 87% yield) as a colorless oil. 1H NMR (400 MHz,CDCl3-d) δ=5.9 (t, J=2.08 Hz, 1H), 3.6 (s, 3H), 3.5 (br s, 2H), 3.0-3.2(m, 2H), 2.6 (br d, J=4.89 Hz, 2H), 2.4-2.6 (m, 2H), 2.1-2.2 (m, 2H),1.4 (s, 9H).

A mixture of solution of tert-butyl5-(methoxymethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(5.00 g, 17.4 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) and 1 Mhydrochloric acid (50.0 mL) was stirred at 100° C. for 2 h. TLC showedthe reaction was completed. The mixture was basified with 15% sodiumhydroxide to PH=9-10 and added another sodium hydroxide (9.28 g, 34.8mmol, 15% purity, 2.00 eq). Then di-tert-butyldicarbonate (6.25 g, 28.6mmol, 1.65 eq) was added and the mixture was stirred at 25° C. foranother 1 h. The mixture was extracted with ethyl acetate (3-20.0 mL).The combined organic layers were washed with water (20.0 mL), dried overanhydrous sodium sulfate, filtered and the filtrate was concentrated toafford a residue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=1/0-5/1) to afford(3aR,5s,6aS)-tert-butyl5-formylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.30 g, 5.43mmol, 31% yield) as a colorless oil and (3aR,5r,6aS)-tert-butyl5-formylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (450 mg, 1.88mmol, 11% yield) as a colorless oil. 1H NMR (400 MHz, Chloroform-d)δ=9.6-9.7 (m, 1H), 3.6 (br s, 2H), 3.2 (br s, 2H), 3.0-3.1 (m, 1H),2.6-2.8 (m, 2H), 2.1-2.2 (m, 2H), 1.7 (br s, 2H), 1.5 (s, 9H).

To a solution of (3aR,5s,6aS)-tert-butyl5-formylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.30 g, 5.43mmol, 1.00 eq) in methanol (20.0 mL) was added sodium borohydride (206mg, 5.43 mmol, 1.00 eq) at 25° C. The mixture was stirred at 25° C. for10 min. The mixture was quenched with saturated ammonium chloride (3.00mL) and concentrated to afford a residue. The residue was extracted withethyl acetate (2×20.0 mL). The combined organic layers were washed withwater (20.0 mL), dried over anhydrous sodium sulfate, filtered and thefiltrate was concentrated to afford (3aR,5s,6aS)-tert-butyl5-(hydroxymethyl) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.10g, 4.56 mmol, 84% yield) as a colorless oil. 1H NMR (400 MHz,Chloroform-d) δ=3.4-3.5 (m, 4H), 3.0-3.1 (m, 2H), 2.6-2.7 (m, 2H), 2.3(dquin, J=14.79, 7.40, 7.40, 7.40, 7.40 Hz, 1H), 1.5-1.7 (m, 4H), 1.4(s, 9H).

To a solution of (3aR,5s,6aS)-tert-butyl5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (600mg, 2.18 mmol, 1.50 eq) andN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(619 mg, 1.45 mmol, 1.00 eq) in dimethylsulfoxide (6.00 mL) was addedpotassium tert-butoxide (489 mg, 4.36 mmol, 3.00 eq). The mixture wasstirred at 25° C. for 12 h. The mixture was diluted with water (10.0 mL)and then filtered. The filter cake was washed with water (10.0 mL),dried in vacuum to afford crude product. The crude product was purifiedby reversed phase (C18, 0.1% hydrochloric acid in water-acetonitrile) toafford (3aR,5s,6aS)-tert-butyl5-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(500 mg, 773 umol, 53% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=11.6 (br s, 1H), 9.5 (s, 1H), 8.9 (s, 1H), 8.7 (br d, J=4.40Hz, 1H), 8.0 (br t, J=7.15 Hz, 1H), 7.9 (d, J=2.45 Hz, 1H), 7.6-7.7 (m,2H), 7.6 (s, 1H), 7.4-7.5 (m, 1H), 7.3-7.4 (m, 1H), 5.4 (s, 2H), 4.2 (brd, J=6.24 Hz, 2H), 3.4-3.5 (m, 2H), 3.0 (br dd, J=11.07, 3.61 Hz, 2H),2.7-2.8 (m, 2H), 2.6-2.6 (m, 1H), 1.6-1.7 (m, 4H), 1.4 (s,9H).

A mixture of (3aR,5s,6aS)-tert-butyl5-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(500 mg, 772 umol, 1.00 eq) in hydrochloric acid (4 M in ethyl acetate,15.0 mL) was stirred at 25° C. for 1 h. The mixture was concentrated toaffordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazolin-4-amine(500 mg, crude, hydrochloride) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=12.1 (br s, 1H), 9.8 (s, 1H), 9.3 (br s, 2H), 8.9 (s, 1H),8.7 (d, J=4.40 Hz, 1H), 8.2 (td, J=7.73, 1.41 Hz, 1H), 8.0 (d, J=2.57Hz, 1H), 7.8 (d, J=7.82 Hz, 1H), 7.7 (s, 1H), 7.7 (dd, J=8.93, 2.57 Hz,1H), 7.6-7.7 (m, 1H), 7.4 (d, J=9.05 Hz, 1H), 5.5 (s, 2H), 4.3 (d,J=6.36 Hz, 2H), 3.3-3.5 (m, 2H), 2.8-2.9 (m, 4H), 2.6-2.7 (m, 1H),1.6-1.8 (m, 4H) MS (ESI) m/z 547.4 [M+H]+

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazolin-4-amine (500 mg, 857 umol, 1.00 eq,hydrochloride) and formaldehyde (37% in water, 938 mg, 11.6 mmol, 861uL, 13.5 eq) in acetonitrile (35.5 mL) was added sodiumtriacetoxyhydroborate (785 mg, 3.70 mmol, 4.32 eq) at 20° C. The mixturewas stirred at 20° C. for 12 h. The mixture was concentrated to afford aresidue. The residue was diluted with water and stirred for 30 min.After filtration, the filter cake was washed with methanol, dried undervacuum to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)-6-nitroquinazolin-4-amine (370 mg, crude) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=10.1 (s, 1H), 9.2 (s, 1H), 8.6-8.6 (m, 2H), 8.0(d, J=2.45 Hz, 1H), 7.9 (td, J=7.64, 1.71 Hz, 1H), 7.7 (dd, J=8.93, 2.45Hz, 1H), 7.6 (d, J=7.82 Hz, 1H), 7.4 (s, 1H), 7.4 (dd, J=6.97, 5.26 Hz,1H), 7.3 (d, J=9.05 Hz, 1H), 5.3 (s, 2H), 4.2 (d, J=6.48 Hz, 2H),2.6-2.7 (m, 2H), 2.5-2.6 (m, 4H), 2.2 (s, 3H), 2.1-2.2 (m, 1H), 1.5-1.7(m, 4H). MS (ESI) m/z 561.3 [M+H]+

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)-6-nitroquinazolin-4-amine (270 mg, 481 umol,1.00 eq) and ammonium chloride (318 mg, 5.95 mmol, 208 uL, 12.4 eq) inmethanol (15.0 mL) and water (15.0 mL) was added powder iron (259 mg,4.63 mmol, 9.63 eq) at 20° C. The mixture was heated to 80° C. andstirred at 80° C. for 1 h. The mixture was concentrated to afford aresidue. The residue was diluted with methanol (30.0 mL) and stirred for20 min. After filtration, the filtrate was concentrated to afford crudeproduct. The crude product was triturated with water (5.00 mL),saturated aqueous sodium carbonate solution (1.00 mL) to affordN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazoline-4,6-diamine(210 mg, 395 umol, 82% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.2 (s, 1H), 8.6-8.6 (m, 1H), 8.3 (s, 1H), 8.0 (d, J=2.57 Hz,1H), 7.9-7.9 (m, 1H), 7.7 (dd, J=8.99, 2.63 Hz, 1H), 7.6-7.6 (m, 1H),7.4-7.4 (m, 2H), 7.2 (d, J=9.05 Hz, 1H), 7.1 (s, 1H), 5.3 (s, 2H), 4.1(br d, J=6.48 Hz, 2H), 2.5-3.0 (m, 6H), 2.3-2.4 (m, 4H), 1.5-1.8 (m,4H). MS (ESI) m/z 531.4 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazoline-4,6-diamine(250 mg, 471 umol, 1.00 eq) and pyridine (149 mg, 1.88 mmol, 4.00 eq)and acrylic acid (0.500 M in dimethylformamide, 1.13 mL, 1.20 eq) indimethylformamide (2.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (271 mg,1.41 mmol, 3.00 eq) in dimethylformamide at 0° C. The mixture wasstirred at 25° C. for 5 h. The mixture was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% FA)-ACN]; B %: 1%-30%, 10 min) to afford crude product (77%purity by HPLC). The crude product was re-purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)-ACN]; B %: 10%-30%, 9 min) and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazolin-6-yl)acrylamide 103 (25.43 mg, 40.1 umol,9% yield, 98% purity, hydrochloride) as a yellow solid. 1H NMR (400 MHz,D2O-d2) δ=8.8 (d, J=5.75 Hz, 1H), 8.8-8.8 (m, 1H), 8.7-8.7 (m, 1H),8.6-8.7 (m, 2H), 8.2 (d, J=8.07 Hz, 1H), 8.1 (t, J=6.91 Hz, 1H), 7.7-7.8(m, 1H), 7.5-7.6 (m, 1H), 7.3-7.4 (m, 2H), 6.5-6.7 (m, 1H), 6.4-6.5 (m,1H), 6.0-6.1 (m, 1H), 5.7 (s, 2H), 4.2-4.4 (m, 2H), 3.8-4.0 (m, 2H),3.3-3.5 (m, 1H), 3.2 (br s, 1H), 3.0-3.1 (m, 2H), 2.9-3.0 (m, 3H),2.7-2.8 (m, 3H), 1.6-2.0 (m, 4H). MS (ESI) m/z 585.1 [M+H]+

104: A mixture of 7-fluoro-6-nitroquinazolin-4-ol (30.0 g, 143 mmol,1.00 eq) and dimethyl formamide (1.05 g, 14.3 mmol, 1.10 mL, 0.100 eq)in sulfurous dichloride (30.0 mL) was stirred at 90° C. for 12 h. Themixture was concentrated to give a 4-chloro-7-fluoro-6-nitroquinazoline(35.0 g, crude) as a yellow solid. MS (ESI) m/z 228.0 [M+H]+

A mixture of 4-chloro-7-fluoro-6-nitro-quinazoline (5.00 g, 21.9 mmol,1.00 eq) and 3-methyl-4-((6-methylpyridin-3-yl)oxy)aniline (5.18 g, 24.2mmol, 1.10 eq) in isopropyl alcohol (50.0 mL) was stirred at 80° C. for1 h. The reaction mixture was concentrated to give a residue. Theresidue was triturated with ethyl acetate (20.0 mL) to give7-fluoro-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(8.00 g, 19.7 mmol, 89% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=11.04 (br s, 1H), 9.77 (d, J=7.8 Hz, 1H), 8.79 (s, 1H), 8.44(d, J=2.8 Hz, 1H), 7.90 (d, J=12.2 Hz, 1H), 7.85-7.77 (m, 2H), 7.76-7.64(m, 2H), 7.13 (d, J=8.7 Hz, 1H), 2.63 (s, 3H), 2.26 (s, 3H). MS (ESI)m/z 406.1 [M+H]+

A mixture of7-fluoro-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(4.00 g, 9.87 mmol, 1.00 eq) and potassium acetate (4.84 g, 49.3 mmol,5.00 eq) in dimethyl formamide (40.0 mL) was stirred at 100° C. for 1 h.The reaction mixture was concentrated to give a residue. The residue wastriturated with water (20.0 mL) to give4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-ol(3.20 g, 7.93 mmol, 80% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.01 (br s, 1H), 9.19 (s, 1H), 8.49 (s, 1H), 8.19 (d, J=2.1Hz, 1H), 7.75 (br s, 1H), 7.68 (br d, J=8.6 Hz, 1H), 7.31-7.18 (m, 2H),7.13 (s, 1H), 6.96 (d, J=8.7 Hz, 1H), 2.44 (s, 3H), 2.21 (s, 3H). MS(ESI) m/z 404.1 [M+H]+

To a solution of4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-ol(2.50 g, 6.20 mmol, 1.00 eq) and pyridine (2.45 g, 30.99 mmol, 2.50 mL,5.00 eq) in dichloromethane (30.0 mL) was added trifluoromethanesulfonicanhydride (3.50 g, 12.4 mmol, 2.05 mL, 2.00 eq) at 0° C. The mixture wasstirred at 20° C. for 1 h. The reaction mixture was concentrated to givea residue. The residue was purified by column chromatography (SiO2,petroleum ether/ethyl acetate=10/1 to 0/1) to give4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (2.00 g, 3.74 mmol, 60% yield) as a yellowsolid. 1H NMR (400 MHz, CDCl3) δ=8.98 (s, 1H), 8.80-8.70 (m, 1H), 8.15(d, J=2.8 Hz, 1H), 7.80 (s, 1H), 7.54 (br s, 1H), 7.41 (br d, J=7.2 Hz,1H), 7.24 (br d, J=7.3 Hz, 1H), 7.17-7.11 (m, 1H), 6.84 (d, J=8.8 Hz,1H), 2.50 (s, 3H), 2.22 (s, 3H). MS (ESI) m/z 536.1 [M+H]+

To a solution of4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (1.00 g, 1.87 mmol, 1.00 eq),(1R,5S,6s)-tert-butyl 6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(503 mg, 2.43 mmol, 1.30 eq), copper(I) iodide (71.1 mg, 373 umol, 0.200eq) and triethylamine (567 mg, 5.60 mmol, 779 uL, 3.00 eq) in dimethylformamide (10.0 mL) was added tetrakis[triphenylphosphine]palladium(0)(216 mg, 186 umol, 0.100 eq) at 15° C. The mixture was stirred at 15° C.for 12 h. The reaction was concentrated to afford a residue. The residuewas triturated with ethyl acetate (200 mL). After filtration, thefiltrate was dried in vacuum to afford crude product. The crude productwas purified by silica gel chromatography (petroleum ether/ethylacetate=1/i to 0/1) to afford (1R,5S,6s)-tert-butyl6-((4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(700 mg, 1.18 mmol, 63% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3)δ=8.94 (s, 1H), 8.79 (s, 1H), 8.56 (br s, 1H), 8.27 (d, J=2.4 Hz, 1H),8.00 (s, 1H), 7.57-7.54 (m, 1H), 7.20-7.08 (m, 2H), 6.90 (d, J=8.7 Hz,1H), 3.85-3.65 (m, 2H), 3.45 (br d, J=11.1 Hz, 2H), 2.56 (s, 3H), 2.29(s, 3H), 2.09 (br s, 2H), 1.54-1.49 (m, 1H), 1.48 (s, 9H). MS (ESI) m/z593.6 [M+H]+

A mixture of (1R,5S,6s)-tert-butyl6-((4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(700 mg, 1.18 mmol, 1.00 eq) in hydrochloric acid/ethyl acetate (4.00 M,10.0 mL, 33.8 eq) was stirred at 25° C. for 0.5 h. The reaction mixturewas concentrated to give a residue. The residue was triturated withethyl acetate (10.0 mL) to give7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(800 mg, crude) as a yellow solid. MS (ESI) m/z 493.4 [M+H]+

A mixture of7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(600 mg, 1.22 mmol, 1.00 eq), sodium borohydride (55.3 mg, 1.46 mmol,1.20 eq) and formaldehyde (195 mg, 6.09 mmol, 246, 5.00 eq) in2,2,2-trifluoroethanol (3.00 mL) was stirred at 60° C. for 2 h. Themixture was concentrated to afford a residue. The residue was dilutedwith saturated sodium carbonate (30.0 mL) and water (10.0 mL), extractedwith ethyl acetate (3-80.0 mL). The combined organic layer was washedwith water (20.0 mL), dried over anhydrous sodium sulfate, filtered andthe filtrate was concentrated to afford7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(350 mg, 690 umol, 57% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=9.44 (s, 1H), 8.67 (s, 1H), 8.20 (d, J=1.5 Hz, 1H), 7.89 (s,1H), 7.76 (br s, 1H), 7.71-7.65 (m, 1H), 7.65-7.60 (m, 1H), 7.60-7.54(m, 1H), 7.25 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 3.03 (d, J=9.2 Hz, 2H),2.45 (s, 3H), 2.30 (br d, J=8.3 Hz, 2H), 2.24 (d, J=3.2 Hz, 6H),1.98-1.86 (m, 3H). MS (ESI) m/z 507.5 [M+H]+

A mixture of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6-nitroquinazolin-4-amine(300 mg, 592 umol, 1.00 eq), iron powder (165 mg, 2.96 mmol, 5.00 eq)and ammonium chloride (158 mg, 2.96 mmol, 5.00 eq) in methanol (10.0 mL)and water (2.00 mL) was stirred at 70° C. for 12 h. The reaction mixturewas added methanol (20.0 mL). The mixture was filtered. The filtrate wasconcentrated to give a residue. The residue was purified by prep-HPLC{column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase. [water(0.225% FA)-ACN]; B %: 1%-30%, 10 min} and lyophilized to give7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N4-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)quinazoline-4,6-diamine (130 mg, 272 umol, 46% yield) as a yellowsolid. 1H NMR (400 MHz, CDCl3) δ=8.55 (s, 1H), 8.27 (d, J=2.6 Hz, 1H),7.78 (s, 1H), 7.63 (br d, J=2.2 Hz, 1H), 7.52 (dd, J=2.6, 8.4 Hz, 1H),7.15-7.10 (m, 2H), 7.01 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 3.33 (d, J=9.8Hz, 2H), 2.58 (br s, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.08(br d, J=2.9 Hz, 1H), 1.98 (br s, 2H). MS (ESI) m/z 477.4 [M+H]+

To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N4-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)quinazoline-4,6-diamine (120 mg, 252 umol, 1.00 eq),triethylamine (50.9 mg, 503 umol, 70.1 uL, 2.00 eq) in dimethylformamide (1.00 mL) was added prop-2-enoyl prop-2-enoate (31.7 mg, 251umol, 3.46 uL, 1.00 eq) at 25° C. The mixture was stirred at 25° C. for2 h. The reaction mixture was filtered. The filtrate was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (10 mM NH4HCO3)-ACN]; B %: 35%-65%, 10 min) and lyophilized togiveN-(7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)acrylamide104 (33.6 mg, 63.3 umol, 25% yield, 100% purity) as an orange solid. 1HNMR (400 MHz, CDCl3) δ=9.03 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.21(d, J=2.7 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.56 (d, J=2.3 Hz, 1H),7.50 (dd, J=2.7, 8.7 Hz, 1H), 7.10-6.97 (m, 2H), 6.84 (d, J=8.7 Hz, 1H),6.55-6.38 (m, 1H), 6.35-6.19 (m, 1H), 5.91-5.75 (m, 1H), 3.09 (d, J=9.3Hz, 2H), 2.46 (s, 3H), 2.35 (br d, J=8.9 Hz, 2H), 2.28 (s, 3H), 2.22 (s,3H), 2.02 (br s, 1H), 1.87 (br s, 2H). MS (ESI) m/z 531.5 [M+H]+

105: A mixture of (1R,5S,6s)-tert-butyl6-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(450 mg, 734 umol, 1.00 eq), iron (205 mg, 3.67 mmol, 5.00 eq) andammonium chloride (353 mg, 6.61 mmol, 9.00 eq) in methanol (2.00 mL) andwater (2.00 mL) was stirred at 80° C. for 2 h. The reaction mixture wasconcentrated to give a residue. The residue was added ethyl acetate(50.0 mL). The mixture was filtered. The filtrate was concentrated togive tert-butyl (1R,5S,6s)-tert-butyl6-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(450 mg, crude) as a yellow solid. MS (ESI) m/z 583.5 [M+H]+

To a solution of (1R,5S,6s)-tert-butyl6-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200mg, 343 umol, 1.00 eq), triethylamine (69.4 mg, 686 umol, 2.00 eq) indimethyl formamide (1.00 mL) was added prop-2-enoyl prop-2-enoate (47.5mg, 377 umol, 1.10 eq) at 25° C. The mixture was stirred at 25° C. for 2h. The mixture was filtered. The filtrate was purified by reversed-phasechromatography (0.1% FA condition) and lyophilized to give(1R,5S,6s)-tert-butyl6-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(90.0 mg, 141 umol, 41.2% yield) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ=9.11 (br s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.62 (br s, 1H), 8.28(br s, 1H), 7.91 (br s, 2H), 7.77 (br d, J=7.2 Hz, 1H), 7.68 (br d,J=10.1 Hz, 2H), 7.54 (br d, J=8.6 Hz, 1H), 7.13-6.94 (m, 1H), 6.61-6.48(m, 1H), 6.46-6.26 (m, 1H), 5.94 (br d, J=10.0 Hz, 1H), 5.32 (s, 2H),3.92-3.66 (m, 2H), 3.48 (br d, J=10.0 Hz, 2H), 2.08 (br s, 2H), 1.52 (brd, J=3.4 Hz, 1H), 1.49 (d, J=2.7 Hz, 9H). MS (ESI) m/z 637.4 [M+H]+

A mixture of (1R,5S,6s)-tert-butyl6-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(70.0 mg, 109 umol, 1.00 eq) and trifluoroacetic acid (2.16 g, 18.9mmol, 1.40 mL, 172 eq) in dichloromethane (3.00 mL) was stirred at 25°C. for 1 h. The reaction mixture was concentrated to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 10u; mobile phase: [water (0.225% FA)-ACN]; B %: 14%-34%, 7.8 min) andlyophilized to giveN-(7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide105 (54.94 mg, 94.2 umol, 85% yield, 100/6 purity, FA) as a yellowsolid. 1H NMR (400 MHz, MeOD) δ=8.66 (s, 1H), 8.56 (br d, J=3.5 Hz, 1H),8.50 (s, 1H), 8.13 (br d, J=11.5 Hz, 1H), 7.98-7.87 (m, 2H), 7.79 (s,1H), 7.72 (d, J=7.9 Hz, 1H), 7.59 (dd, J=2.6, 8.9 Hz, 1H), 7.40 (dd,J=5.1, 6.9 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.63-6.53 (m, 1H), 6.52-6.44(m, 1H), 5.95-5.83 (m, 1H), 5.27 (s, 2H), 3.63-3.50 (m, 4H), 2.37 (br s,2H), 1.78 (t, J=3.7 Hz, 1H). MS (ESI) m/z 537.3 [M+H]+

106: To a solution of 4-phenoxyaniline (5.00 g, 27.0 mmol, 1.00 eq) inpropan-2-ol (100 mL) was added 4-chloro-7-fluoro-6-nitro-quinazoline(6.76 g, 29.7 mmol, 1.10 eq). The mixture was stirred at 90° C. for 12h. The mixture was concentrated in vacuum to afford crude product. Theresidue was triturated with petroleum ether/ethyl acetate=5/1 (50.0 mL),filtered and dried under reduced pressure to afford7-fluoro-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine (11.0 g, crude)as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=11.65 (br s, 1H), 9.84(d, J=7.7 Hz, 1H), 8.87 (s, 1H), 7.96 (d, J=11.9 Hz, 1H), 7.79-7.76 (m,1H), 7.76-7.73 (m, 1H), 7.46-7.40 (m, 2H), 7.21-7.15 (m, 1H), 7.15-7.13(m, 1H), 7.12-7.10 (m, 1H), 7.08 (d, J=1.0 Hz, 1H), 7.06 (d, J=0.9 Hz,1H). MS (ESI) m/z 376.9 [M+H]+

To a solution of 7-fluoro-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine(10.0 g, 26.6 mmol, 1.00 eq) in N,N-dimethylformamide (100 mL) was addedpotassium acetate (13.0 g, 133 mmol, 5.00 eq). The mixture was stirredat 100° C. for 2 h. The mixture was concentrated in vacuum. The residuewas triturated with water (200 mL). After filtration, the filter cakewas washed with water (100 mL) and dried in vacuum to afford6-nitro-4-((4-phenoxyphenyl)amino)quinazolin-7-ol (11.0 g, crude) as ared solid. 1H NMR (400 MHz, DMSO-d6) δ=8.87 (s, 1H), 8.24 (s, 1H), 7.81(s, 1H), 7.79 (s, 1H), 7.40-7.36 (m, 2H), 7.18-7.06 (m, 2H), 7.06-6.97(m, 5H), 6.65 (s, 1H).

To a solution of 6-nitro-4-(4-phenoxyanilino)quinazolin-7-ol (10.0 g,26.7 mmol, 1.00 eq) and pyridine (10.6 g, 134 mmol, 10.8 mL, 5.00 eq) indichloromethane (200 mL) was added trifluoromethanesulfonic anhydride(15.1 g, 53.4 mmol, 8.81 mL, 2.00 eq) at 0° C. The mixture was stirredat 25° C. for 2 h. The mixture was partitioned between dichloromethane(200 mL) and water (100 mL). The aqueous phase was extracted withdichloromethane (2×100 mL). The combined organic phase was dried overanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=1/0 to 8/1) to afford6-nitro-4-((4-phenoxyphenyl)amino)quinazolin-7-yltrifluoromethanesulfonate (3.10 g, 6.12 mmol, 22% yield) as a brownsolid. 1H NMR (400 MHz, DMSO-d6) δ=10.64 (s, 1H), 9.75 (s, 1H), 8.75 (s,1H), 8.03 (s, 1H), 7.83-7.80 (m, 1H), 7.80-7.77 (m, 1H), 7.44-7.39 (m,2H), 7.19-7.13 (m, 1H), 7.13-7.08 (m, 2H), 7.07-7.03 (m, 2H). MS (ESI)m/z 507.1 [M+H]+

To a solution of 6-nitro-4-((4-phenoxyphenyl)amino)quinazolin-7-yltrifluoromethanesulfonate (1.50 g, 2.96 mmol, 1.00 eq) inN,N-dimethylformamide (15.0 mL) was added tert-butyl6-ethynyl-3-azabicyclo[3.1.0] hexane-3-carboxylate (920 mg, 4.44 mmol,1.50 eq), copper(i) iodide (282 mg, 1.48 mmol, 0.500 eq), triethylamine(899 mg, 8.88 mmol, 1.24 mL, 3.00 eq) andtetrakis[triphenylphosphine]palladium(0) (342 mg, 0.296 mmol, 0.100 eq)at 25° C. under nitrogen. The mixture was stirred at 25° C. for 12 h.The mixture was concentrated in vacuum. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/0 to 1/1) toafford (1R,5S,6s)-tert-butyl6-((6-nitro-4-((4-phenoxyphenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(1.43 g, 2.54 mmol, 85% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d6) δ=10.37 (br s, 1H), 9.43 (s, 1H), 8.66 (br s, 1H), 7.90 (br s,1H), 7.80 (br d, J=8.7 Hz, 2H), 7.40 (br t, J=7.8 Hz, 2H), 7.14 (br t,J=7.3 Hz, 1H), 7.08 (br d, J=8.8 Hz, 2H), 7.04 (br d, J=8.2 Hz, 2H),3.56 (br d, J=11.0 Hz, 2H), 3.37 (br s, 2H), 2.09 (br s, 2H), 1.47 (brs, 1H), 1.39 (s, 9H). MS (ESI) m/z 564.3 [M+H]+

A mixture of (1R,5S,6s)-tert-butyl6-((6-nitro-4-((4-phenoxyphenyl)amino)quinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(1.33 g, 2.36 mmol, 1.00 eq) in 4.00 M hydrochloric acid/ethyl acetate(15.0 mL) was stirred at 25° C. for 1 h. The mixture was concentrated invacuum. The residue was triturated with ethyl acetate (30.0 mL). Afterfiltration, the filter cake was dried in vacuum to afford7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine(1.00 g, 2.00 mmol, 84% yield, hydrochloric acid) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=11.14 (br s, 1H), 9.59 (s, 1H), 9.48 (br s,1H), 9.30 (br s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.76 (s,1H), 7.45-7.39 (m, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.13-7.09 (m, 2H), 7.06(dd, J=1.0, 8.6 Hz, 2H), 3.47 (dd, J=6.1, 11.8 Hz, 2H), 3.42-3.34 (m,2H), 2.31 (br s, 2H), 2.15 (t, J=3.6 Hz, 1H).

To a solution of7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine (1.00 g, 2.00 mmol, 1.00 eq, hydrochloric acid) andparaformaldehyde (300 mg, 9.99 mmol, 5.00 eq) in trifluoroethanol (15.0mL) was added sodium borohydride (151 mg, 4.00 mmol, 2.00 eq). Themixture was stirred at 60° C. for 12 h. The mixture was concentrated invacuum. The reaction mixture was partitioned between ethyl acetate (50.0mL) and water (30.0 mL). The organic phase was separated, washed withwater (2×20.0 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue to afford7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine (1.00 g, crude)as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ=10.36 (s, 1H), 9.42 (s,1H), 8.70-8.58 (m, 1H), 7.90-7.85 (m, 1H), 7.82 (s, 1H), 7.80 (s, 1H),7.41-7.38 (m, 2H), 7.17-7.13 (m, 1H), 7.10-7.07 (m, 2H), 7.04 (br d,J=7.6 Hz, 2H), 3.02 (d, J=9.2 Hz, 2H), 2.31-2.27 (m, 2H), 2.23 (s, 3H),1.96-1.88 (m, 3H).

To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine(900 mg, 1.88 mmol, 1.00 eq) and iron powder (737 mg, 13.2 mmol, 7.00eq) in methanol (45.0 mL) was added a solution of ammonium chloride (907mg, 17.0 mmol, 9.00 eq) in water (9.00 mL). The mixture was stirred at80° C. for 2 h. The residue was added methanol (100 mL) and stirred at55° C. for 0.5 h, then filtered. The filtrate was concentrated to afforda residue. The residue was triturated with water (30.0 mL) and saturatedsodium carbonate (2.00 mL). After filtration the filter cake was washedwith methanol (100 mL). The filtrate was concentrated in vacuum. Thesolid was purified by prep-HPLC (Phenomenex Synergi C18 150*25*10 um,water (0.1% FA)-ACN) to afford7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N4-(4-phenoxyphenyl)quinazoline-4,6-diamine(360 mg, 0.804 mmol, 42% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d6) δ=9.45 (s, 1H), 8.28 (s, 1H), 7.84-7.83 (m, 1H), 7.82-7.80 (m,1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.41-7.36 (m, 2H), 7.14-7.09 (m, 1H),7.06-7.03 (m, 2H), 7.02-6.99 (m, 2H), 5.53 (s, 2H), 3.01 (d, J=9.1 Hz,2H), 2.28 (br d, J=8.8 Hz, 2H), 2.23 (s, 3H), 1.98-1.95 (m, 2H),1.94-1.90 (m, 1H). MS (ESI) m/z 448.3 [M+H]+

To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N4-(4-phenoxyphenyl)quinazoline-4,6-diamine (150 mg, 0.335 mmol, 1.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (643 mg,3.35 mmol, 10.0 eq) and pyridine (265 mg, 3.35 mmol, 0.271 mL, 10.0 eq)in N,N-dimethylformamide (3.00 mL) was added acrylic acid (242 mg, 3.35mmol, 10.0 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. Themixture was quenched by methanol (2.00 mL) and concentrated in vacuum.The residue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN]; B %:58%-88%, 1 min) and lyophilized to affordN-(7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-4-((4-phenoxyphenyl)amino)quinazolin-6-yl)acrylamide106 (21.18 mg, 41.8 umol, 99% purity, 12% yield) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=9.88 (s, 1H), 9.85 (s, 1H), 8.73 (s, 1H), 8.51(s, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 7.40 (t, J=7.9 Hz, 2H),7.13 (t, J=7.3 Hz, 1H), 7.06 (d, J=8.9 Hz, 2H), 7.02 (d, J=7.7 Hz, 2H),6.63 (dd, J=10.2, 17.1 Hz, 1H), 6.33 (dd, J=1.8, 17.1 Hz, 1H), 5.85 (dd,J=1.8, 10.2 Hz, 1H), 3.00 (d, J=9.2 Hz, 2H), 2.28 (br d, J=8.8 Hz, 2H),2.23 (s, 3H), 1.92 (br s, 2H), 1.90 (br d, J=3.2 Hz, 1H). MS (ESI) m/z502.3 [M+H]+

107: A mixture ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazoline-4,6-diamine (70.0 mg, 140 umol,1.00 eq), but-2-ynoic acid (118 mg, 1.41 mmol, 10.0 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (270 mg, 1.41 mmol, 10.0eq) in pyridine (1.00 mL) was stirred at 25° C. for 0.5 h. The reactionmixture was filtered. The filtrate was purified by prep-HPLC (column:Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-68%, 10 min) and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazolin-6-yl)but-2-ynamide107 (5.37 mg, 9.54 umol, 6.7% yield, 100% purity) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ=10.26 (br s, 1H), 9.82 (s, 1H), 8.60 (d, J=4.1Hz, 1H), 8.53 (d, J=14.1 Hz, 2H), 8.01 (d, J=2.5 Hz, 1H), 7.89 (dt,J=1.8, 7.7 Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J=2.6, 8.9 Hz, 1H), 7.59 (d,J=7.9 Hz, 1H), 7.38 (dd, J=4.9, 6.6 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H),5.30 (s, 2H), 3.03 (d, J=9.1 Hz, 2H), 2.31 (br d, J=8.8 Hz, 2H), 2.24(s, 3H), 2.09 (br s, 3H), 1.94 (br s, 2H), 1.90-1.86 (m, 1H). MS (ESI)m/z 563.5 [M+H]+108: To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N4-(4-phenoxyphenyl)quinazoline-4,6-diamine (140 mg, 0.313 mmol, 1.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600 mg,3.13 mmol, 10.0 eq) and pyridine (247 mg, 3.13 mmol, 0.253 mL, 10.0 eq)in N,N-dimethylformamide (3.00 mL) was added but-2-ynoic acid (263 mg,3.13 mmol, 10.0 eq). The mixture was stirred at 25° C. for 2 h. Themixture was quenched by methanol (2.00 mL) and concentrated in vacuum.The residue was purified by prep-HPLC (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 13%-43%, 10 min imin)and lyophilized to affordN-(7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-4-((4-phenoxyphenyl)amino)quinazolin-6-yl)but-2-ynamide108 (20.39 mg, 36.07 umol, 11% yield, 99/o purity, formic acid) as ayellow solid. 1H NMR (400 MHz, DMSO-d6) δ=10.26 (br s, 1H), 9.85 (s,1H), 8.54 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 7.80 (s,1H), 7.74 (s, 1H), 7.43-7.36 (m, 2H), 7.13 (t, J=7.4 Hz, 1H), 7.09-7.04(m, 2H), 7.02 (dd, J=1.0, 8.7 Hz, 2H), 3.02 (d, J=9.2 Hz, 2H), 2.31 (brd, J=9.4 Hz, 2H), 2.24 (s, 3H), 2.08 (br s, 3H), 1.93 (br s, 2H),1.90-1.86 (m, 1H). MS (ESI) m/z 514.3 [M+H]+109: To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine(200 mg, 394 umol, 1.00 eq), pyridine (62.4 mg, 789 umol, 63.7 uL, 2.00eq) and 2-fluoroacrylic acid (107 mg, 1.18 mmol, 3.00 eq) in dimethylformamide (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (454 mg,2.37 mmol, 6.00 eq) at 25° C. in portions. The mixture was stirred at25° C. for 12 h. The reaction mixture was filtered. The filtrate waspurified by prep-HPLC (column. Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.05% ammonia hydroxide v/v)−ACN]; B %: 37%-67%, 1 min) to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoroacrylamide 109(32.12 mg, 54.9 umol, 14% yield, 99% purity) as an off-white solid. 1HNMR (400 MHz, CDCl3) δ=9.10 (br d, J=4.4 Hz, 1H), 9.03 (s, 1H), 8.67 (s,1H), 8.62 (d, J=4.4 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.83-7.74 (m, 1H),7.69 (br d, J=7.6 Hz, 2H), 7.54 (dd, J=8.8, 2.6 Hz, 1H), 7.30 (s, 1H),7.26 (br d, J=6.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 5.99-5.80 (m, 1H),5.37 (dd, J=15.2, 3.8 Hz, 1H), 5.32 (s, 2H), 4.38 (t, J=5.4 Hz, 2H),3.80-3.73 (m, 4H), 2.94 (t, J=5.4 Hz, 2H), 2.66-2.60 (m, 4H). MS (ESI)m/z 579.4 [M+H]+110: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(2.00 g, 4.70 mmol, 1.00 eq), 1-methylpiperidin-4-ol (1.08 g, 9.39 mmol,1.10 mL, 2.00 eq) and potassium tert-butoxide (2.11 g, 18.7 mmol, 4.00eq) in dimethylsulfoxide (20.0 mL) was stirred at 25° C. for 1 h. To themixture was added water (20 mL). The mixture was filtered. The filtercake was dried to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpiperidin-4-yl)oxy)-6-nitroquinazolin-4-amine(2.00 g, 3.84 mmol, 81% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-d6) δ=10.02 (br s, 1H), 9.16 (s, 1H), 8.61 (br s, 2H), 8.01 (br s,1H), 7.89 (br t, J=7.4 Hz, 1H), 7.69 (br d, J=8.2 Hz, 1H), 7.59 (br d,J=7.7 Hz, 1H), 7.50 (s, 1H), 7.42-7.33 (m, 1H), 7.28 (br d, J=8.9 Hz,1H), 5.30 (s, 2H), 4.89 (br s, 1H), 2.55 (br s, 2H), 2.32 (br d, J=7.7Hz, 2H), 2.18 (s, 3H), 1.97 (br s, 2H), 1.77 (br s, 2H). MS (ESI) m/z521.3 [M+H]+

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpiperidin-4-yl)oxy)-6-nitroquinazolin-4-amine(1.60 g, 3.07 mmol, 1.00 eq), iron (857 mg, 15.3 mmol, 5.00 eq) andammonium chloride (1.48 g, 27.6 mmol, 9.00 eq) in methanol (5.00 mL) andwater (5.00 mL) was stirred at 80° C. for 2 h. The reaction mixture wasconcentrated to give a residue. The residue was added ethyl acetate (500mL). The reaction mixture was filtered. The filtrate was concentrated togiveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpiperidin-4-yl)oxy)quinazoline-4,6-diamine(1.50 g, crude) as a yellow solid. MS (ESI) m/z 491.3 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpiperidin-4-yl)oxy)quinazoline-4,6-diamine(500 mg, 1.02 mmol, 1 eq), pyridine (241 mg, 3.06 mmol, 3.00 eq) andacrylic acid (88.1 mg, 1.22 mmol, 1.20 eq) in dimethyl formamide (3.00mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (585 mg,3.06 mmol, 3.00 eq) at 25° C. The reaction mixture was stirred at 25° C.for 1 h. The reaction mixture was filtered. The filtrate was purified byprep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase:[water (0.225% FA)-ACN]; B %: 10%-40%, 10 min) and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)acrylamide110 (190.01 mg, 321 umol, 31% yield, 100% purity, FA) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ=9.68 (br s, 1H), 9.53 (s, 1H), 8.83 (s, 1H),8.60 (d, J=4.8 Hz, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.00 (d, J=2.6 Hz,1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd, J=2.6, 8.9 Hz, 1H), 7.59(d, J=7.8 Hz, 1H), 7.37 (dd, J=5.1, 7.3 Hz, 1H), 7.32 (s, 1H), 7.25 (d,J=9.0 Hz, 1H), 6.71 (dd, J=10.3, 17.0 Hz, 1H), 6.33 (dd, J=1.8, 17.0 Hz,1H), 5.83 (dd, J=1.8, 10.1 Hz, 1H), 5.29 (s, 2H), 4.80-4.67 (m, 1H),2.76-2.64 (m, 2H), 2.34 (br dd, J=2.1, 4.0 Hz, 2H), 2.25 (s, 3H),2.10-1.97 (m, 2H), 1.91-1.77 (m, 2H). MS (ESI) m/z 545.3 [M+H]+

111: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine(1.00 g, 2.06 mmol, 1.00 eq), piperidin-4-ol (416 mg, 4.11 mmol, 2.00eq), potassium carbonate (853 mg, 6.17 mmol, 3.00 eq) in dimethylformamide (20.0 mL) was stirred at 80° C. for 5 h under nitrogenatmosphere. The reaction mixture was diluted with water (50 mL) andfiltered. The filter cake was dried to give1-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)piperidin-4-ol (800 mg, crude) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ=8.74 (s, 1H), 8.62 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 7.88 (d,J=2.6 Hz, 1H), 7.83-7.75 (m, 1H), 7.71-7.52 (m, 2H), 7.49 (dd, J=8.8,2.6 Hz, 1H), 7.41 (s, 1H), 7.27 (br s, 1H), 7.05 (d, J=9.0 Hz, 1H), 5.33(s, 2H), 4.49-4.33 (m, 2H), 3.75 (br s, 1H), 2.99-2.90 (m, 3H),2.45-2.33 (m, 2H), 1.94 (br d, J=9.6 Hz, 1H), 1.56 (br s, 2H). MS (ESI)m/z 551.2 [M+H]+

A mixture of1-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)piperidin-4-ol (400 mg, 726 umol, 1.00 eq), iron powder (202 mg,3.63 mmol, 5.00 eq), ammonium chloride (194 mg, 3.63 mmol, 5.00 eq) inmethanol (20.0 mL) and water (10.0 mL) was stirred at 80° C. for 2 hunder nitrogen atmosphere. The reaction mixture was filtered and washedwith methanol. The combined filtrate was concentrated under reducedpressure to give a residue. The residue was triturated with water (20mL) and filtered. The filter cake was dried to give1-(2-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-4-ol(300 mg, crude) as a yellow solid. MS (ESI) m/z 521.4 [M+H]+

To a solution of1-(2-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-4-ol (200 mg, 384 umol, 1.00 eq), acrylic acid (41.5 mg,576 umol, 39.5 uL, 1.50 eq) and pyridine (60.7 mg, 768 umol, 62.0 uL,2.00 eq) in dimethyl formamide (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (368 mg,1.92 mmol, 5.00 eq) at 25° C. in portions. The mixture was stirred at25° C. for 1 h. The reaction mixture was filtered. The filtrate waspurified by prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.05% ammonia hydroxide v/v)−ACN]; B %: 29/o-59/o, 1 min) toafforded N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(4-hydroxypiperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide111 (52.83 mg, 91.9 umol, 24% yield, 100% purity) as an off-white solid.1H NMR (400 MHz, CDCl3) δ=9.15 (s, 1H), 9.11 (s, 1H), 8.64 (s, 1H), 8.62(br d, J=4.8 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.82-7.74(m, 1H), 7.71-7.65 (m, 1H), 7.54 (dd, J=8.8, 2.8 Hz, 1H), 7.23-7.28 (m,2H), 7.01 (d, J=8.8 Hz, 1H), 6.51 (d, J=6.2 Hz, 2H), 5.87-5.81 (m, 1H),5.31 (s, 2H), 4.33 (t, J=5.3 Hz, 2H), 3.82 (br d, J=4.8 Hz, 1H), 2.92(br t, J=5.2 Hz, 4H), 2.35 (br t, J=9.6 Hz, 2H), 1.97 (br d, J=9.4 Hz,2H), 1.73-1.57 (m, 2H). MS (ESI) m/z 575.4 [M+H]+

112: Sodium (139 mg, 6.06 mmol, 144 uL, 5.00 eq) was dissolved inmethanol (5.00 mL) at 0° C. and the mixture was stirred at 25° C. for0.5 h. Then to the mixture was added (E)-4-bromobut-2-enoic acid (200mg, 1.21 mmol, 1.00 eq) in portions. The mixture was stirred at 70° C.for 2 h. The mixture was concentrated to give residue. The residue wasdiluted with water (20 mL) and added 1 M hydrochloric acid to adjustpH=1. The mixture was extracted with ethyl acetate (3-20.0 mL). Thecombined organic layer was washed with brine (20 mL) and dried oversodium sulfate, filtered and concentrated to give(E)-4-methoxybut-2-enoic acid (90.0 mg, 775 umol, 64% yield) as a whitesolid. 1H NMR (400 MHz, DMSO-d6) δ=12.31 (br s, 1H), 6.81 (dt, J=15.8,4.2 Hz, 1H), 5.91 (dt, J=15.8, 2.0 Hz, 1H), 4.06 (dd, J=4.2, 2.0 Hz,2H), 3.29 (s, 3H).

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine(200 mg, 394 umol, 1.00 eq), (E)-4-methoxybut-2-enoic acid (68.7 mg, 592umol, 1.50 eq) and pyridine (93.6 mg, 1.18 mmol, 95.5 uL, 3.00 eq) indimethyl formamide (3.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (303 mg, 1.58 mmol, 4.00eq) in portions. The mixture was stirred at 25° C. for 1 h. The mixturewas filtered and the filtrate was purified by prep-HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.225%FA)-ACN]; B %: 7%-37%, 10 min) and lyophilized to give(E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-4-methoxybut-2-enamide 112 (21.50 mg, 32.7 umol, 8%yield, 99% purity, FA) as a yellow solid. 1H NMR (400 MHz, DMSO-d6)δ=9.68 (s, 1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.63-8.59 (m, 1H), 8.49 (s,1H), 8.38 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.89 (td, J=7.8, 1.8 Hz, 1H),7.70 (dd, J=9.0, 2.6 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.38 (dd, J=7.0,5.4 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.90-6.81 (m, 1H),6.57 (br d, J=15.6 Hz, 1H), 5.29 (s, 2H), 4.34 (t, J=5.8 Hz, 2H), 4.14(dd, J=4.2, 1.8 Hz, 2H), 3.61-3.56 (m, 4H), 3.35 (br s, 3H), 2.84 (t,J=5.8 Hz, 2H), 2.53-2.52 (m, 4H). MS (ESI) m/z 605.4 [M+H]+

113: To a solution of7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(400 mg, 800 umol, 1.00 eq), oxetan-3-one (281 mg, 3.90 mmol, 5.00 eq)in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was addedtriethylamine (499 mg, 4.93 mmol, 6.32 eq), acetic acid (720 mg, 12.0mmol, 15.4 eq) at 20° C. The mixture was stirred at 60° C. for 0.5 h.Sodium cyanoborohydride (245 mg, 3.90 mmol, 5.00 eq) was added at 20° C.The mixture was stirred at 60° C. for 1 h. The mixture was concentratedin vacuo to give a residue. The residue was extracted with ethylacetate/methanol (5/1, 3×20.0 mL), washed with brine (3×20.0 mL), anddried over anhydrous sodium sulfate, filtered and concentrated to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(((1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazolin-4-amine(0.350 g, 615 umol, 78% yield) as a brown solid. 1H NMR (400 MHz,DMSO-d6) δ=10.32 (s, 1H), 9.40 (s, 1H), 8.68 (s, 1H), 8.60 (br d, J=4.8Hz, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.91 (s, 1H), 7.89-7.84 (m, 1H), 7.70(dd, J=2.5, 9.0 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.37 (dd, J=5.1, 7.0Hz, 1H), 7.30 (d, J=9.2 Hz, 1H), 5.30 (s, 2H), 4.53 (t, J=6.6 Hz, 2H),4.43 (t, J=6.0 Hz, 2H), 3.72 (quin, J=6.3 Hz, 1H), 3.06 (d, J=9.2 Hz,2H), 2.39 (br d, J=8.4 Hz, 2H), 2.00 (br s, 2H), 1.93 (br d, J=2.9 Hz,1H). MS (ESI) m/z 569.4 [M+H]+

To a suspension ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(((1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazolin-4-amine(0.320 g, 562 umol, 1.00 eq), iron powder (220 mg, 3.94 mmol, 7.00 eq)in tetrahydrofuran (10.0 mL), methanol (10.0 mL) was added ammoniumchloride (211 mg, 3.94 mmol, 7.00 eq) in water (5.00 mL). The mixturewas stirred at 80° C. for 2 h. The mixture was added methanol (50.0 mL)and stirred at 55° C. for 0.5 h. After filtration, the filtrate wasconcentrated to afford a residue. The residue was triturated with water(10.0 mL), saturated sodium carbonate (5.00 mL) to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazoline-4,6-diamine(0.300 g, crude) as a yellow solid. MS (ESI) m/z 539.1 [M+H]+

To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(((1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazoline-4,6-diamine (150 mg, 278 umol,1.00 eq), acrylic acid (40.1 mg, 557 umol, 2.00 eq) and pyridine (44.0mg, 557 umol, 2.00 eq) in dimethylformamide (3.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (267 mg,1.39 mmol, 5.00 eq) at 25° C. in portions. The mixture was stirred at25° C. for 0.5 h. The reaction mixture was filtered. The filtrate waspurified by prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-acetonitrile]; B %: 38%-68%, 1 min)to give N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(((1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)quinazolin-6-yl)acrylamide113 (63.06 mg, 105 umol, 38% yield, 99% purity) as a yellow solid. 1HNMR (400 M Hz, CDCl3) δ=9.07 (s, 1H), 8.66 (s, 1H), 8.61 (d, J=4.5 Hz,1H), 8.33 (s, 1H), 8.03 (br s, 1H), 7.92-7.85 (m, 2H), 7.82-7.74 (m,1H), 7.72-7.63 (m, 1H), 7.54 (dd, J=2.6, 8.8 Hz, 1H), 7.26 (br d, J=6.7Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 6.56-6.47 (m, 1H), 6.38 (d, J=10.3 Hz,1H), 5.93 (d, J=10.5 Hz, 1H), 5.30 (s, 2H), 4.75-4.66 (m, 2H), 4.60 (t,J=6.1 Hz, 2H), 3.79 (t, J=6.3 Hz, 1H), 3.15 (d, J=8.9 Hz, 2H), 2.47 (brd, J=8.4 Hz, 2H),2.14 (t, J=3.1 Hz, 1H), 1.99 (br s, 2H). MS (ESI) m/z593.4 [M+H]+

114: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine(600 mg, 1.23 mmol, 1.00 eq) in dimethyl formamide (6.00 mL) was addedpotassium carbonate (511 mg, 3.70 mmol, 3.00 eq) and 4-methoxypiperidine(284 mg, 2.47 mmol, 2.00 eq), then the mixture was stirred at 80° C. for8 h. The mixture was poured into water (30.0 mL) to give someprecipitate. Then the precipitate was washed with water (5.00 mL) anddried under vacuum to give the crude productN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methoxypiperidin-1-yl)ethoxy)-6-nitroquinazolin-4-amine(660 mg, 1.17 mmol, 94% yield) as a yellow solid was used into the nextstep directly without further purification. MS (ESI) m/z 565.3 [M+H]+

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methoxypiperidin-1-yl)ethoxy)-6-nitroquinazolin-4-amine(560 mg, 991 umol, 1.00 eq) in methanol (6.00 mL) and water (1.50 mL)was added iron powder (276 mg, 4.96 mmol, 5.00 eq) and ammonium chloride(159 mg, 2.97 mmol, 3.00 eq). Then the mixture was stirred at 80° C. for2 h. The mixture was filtered and the filtrate was extracted with ethylacetate (4×5.00 mL). All organic phases were combined, washed with brine(5.00 mL), dried over anhydrous sodium sulfate and concentrated undervacuum to give the crude productN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methoxypiperidin-1-yl)ethoxy)quinazoline-4,6-diamine(270 mg, 388 umol, 39% yield, 77% purity) as a yellow solid was usedinto next step without further purification. MS (ESI) m/z 535.3 [M+H]+To a solution ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methoxypiperidin-1-yl)ethoxy)quinazoline-4,6-diamine (250 mg, 467 umol, 1.00 eq) in dimethylformamide (2.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (358 mg,1.87 mmol, 4.00 eq), acrylic acid (101 mg, 1.40 mmol, 96.2 uL, 3.00 eq)and pyridine (110 mg, 1.40 mmol, 113 uL, 3.00 eq) at 30° C. and themixture was stirred at 30° C. for 1 h. The mixture was diluted withmethanol (1.00 mL) and sent for purification. The mixture was purifiedby prep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)−ACN]; B %: 43%-73%, 1 min) and prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 23%-53%, 9 min) again to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(4-methoxypiperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide114 (27.56 mg, 43.39 umol, 9/o yield, 100% purity, FA) as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) δ=9.68 (s, 1H), 9.61 (s, 1H), 8.85 (s,1H), 8.61 (br d, J=4.2 Hz, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 8.00 (d,J=2.6 Hz, 1H), 7.89 (dt, J=1.6, 7.6 Hz, 1H), 7.70 (dd, J=2.6, 8.8 Hz,1H), 7.60 (d, J=7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (s, 1H), 7.26 (d,J=9.0 Hz, 1H), 6.69 (dd, J=10.4, 16.8 Hz, 1H), 6.32 (dd, J=1.8, 17.2 Hz,1H), 5.89-5.76 (m, 1H), 5.29 (s, 2H), 4.32 (br t, J=5.6 Hz, 2H), 3.22(s, 3H), 3.17-3.15 (m, 1H), 2.82 (br t, J=5.6 Hz, 4H), 2.25 (br t,J=10.0 Hz, 2H), 1.82 (br d, J=9.8 Hz, 2H), 1.48-1.37 (m, 2H). MS (ESI)m/z 589.4 [M+H]+

115: Synthesized according to general procedure B, wherein in step B.1ethane-1,2-diol was used; in step B.2 variant ii) was used, in step B.3the nucleophile is 1-methyl-1,6-diazaspiro[3.3]heptane, in step B.4variant ii) was used and variant i) was used in step B.5; and 29%overall yield from IX. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 1H), 9.63(s, 1H), 8.82 (s, 1H), 8.68-8.56 (m, 1H), 8.50 (s, 1H), 8.00 (d, J=2.6Hz, 1H), 7.89 (br d, J=1.7 Hz, 1H), 7.70 (dd, J=2.6, 9.0 Hz, 1H), 7.60(d, J=7.8 Hz, 1H), 7.42-7.33 (m, 1H), 7.26 (t, 0.1=4.5 Hz, 2H), 6.68(dd, J=10.3, 17.0 Hz, 1H), 6.33 (dd, J=1.8, 17.1 Hz, 1H), 5.88-5.77 (m,1H), 5.29 (s, 2H), 4.19 (br t, J=5.3 Hz, 2H), 3.36-3.34 (m, 2H), 3.22(br d, J=8.7 Hz, 2H), 2.96 (t, J=6.7 Hz, 2H), 2.82 (br t, J=5.3 Hz, 2H),2.19 (s, 3H), 2.15 (t, J=6.7 Hz, 2H). MS (ESI) m/z 586.3 [M+1]⁺116: To the mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.00 g, 2.35 mmol, 1.00 eq), obtained by general procedure A (in stepA.2 the free amine is 3-chloro-4-(pyridin-2-ylmethoxy)aniline) andtert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (660 mg, 3.52 mmol,1.50 eq) in dimethylsulfoxide (15.0 mL) was added potassium2-methylpropan-2-olate (1.05 g, 9.39 mmol, 4.00 eq) in several portionsat 25° C. The mixture was stirred at 25° C. for 2 h. The reactionmixture was concentrated to dryness to give a residue. The residue wastriturated with water (70.0 mL). After filtration, the filter cake waswashed with water (20.0 mL), dried under vacuum to afford tert-butyl2-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(1.10 g, 1.85 mmol, 79% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=10.10 (br s, 1H), 9.25 (s, 1H), 8.65-8.57 (m, 2H), 8.01 (d,J=2.0 Hz, 1H), 7.89 (br t, J=7.2 Hz, 1H), 7.70 (dd, J=2.0, 8.9 Hz, 1H),7.59 (br d, 1=7.8 Hz, 1H), 7.52 (s, 1H), 7.43-7.35 (m, 1H), 7.29 (d,J=8.8 Hz, 1H), 5.30 (s, 2H), 4.65 (br d, J=9.0 Hz, 1H), 4.53 (br s, 1H),4.36 (br d, J=9.4 Hz, 1H), 3.76 (br s, 2H), 2.35 (br d, J=10.5 Hz, 1H),2.23 (br s, 1H), 1.30 (s, 10H). MS (ESI) m/z 615.2 [M+H]⁺

To the solution of tert-butyl2-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(1.10 g, 1.85 mmol, 1.00 eq) in dichloromethane (10.0 mL) was addedhydrochloride/ethyl acetate (4 M, 10.00 mL, 21.6 eq) at 25° C. Themixture was stirred at 25° C. for 2 h. The reaction mixture wasconcentrated to dryness to give a residue. The residue was trituratedwith saturated solution of sodium bicarbonate (30.0 mL). Afterfiltration, the filter cake was washed with water (30.0 mL), dried invacuum to give7-(azetidin-2-ylmethoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(880 mg, 1.79 mmol, 96% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.19 (br s, 1H), 8.60 (br d, J=4.4 Hz, 1H), 8.50 (br s, 1H),7.98 (br d, J=3.8 Hz, 1H), 7.88 (br t, J=7.8 Hz, 1H), 7.69-7.56 (m, 2H),7.42-7.33 (m, 2H), 7.22 (br d, J=8.8 Hz, 1H), 5.28 (s, 2H), 4.49-4.31(m, 1H), 4.48-4.23 (m, 1H), 4.28-4.08 (m, 1H), 3.65-3.46 (m, 1H),3.43-3.41 (m, 1H), 2.32-2.01 (m, 2H). MS (ESI) m/z 493.0 [M+H]⁺

To the mixture of7-(azetidin-2-ylmethoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(500 mg, 1.01 mmol, 1.00 eq) and paraformaldehyde (153 mg, 5.10 mmol,5.02 eq) in trifluoroethanol (6.00 mL) was added sodium borohydride(80.0 mg, 2.11 mmol, 2.08 eq) at 25° C. The mixture was stirred at 60°C. for 2 h. The mixture was concentrated to give a residue. The residuewas triturated with water (15.0 mL). After filtration, the filter cakewas washed with water (10.0 mL), dried under vacuum to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazetidin-2-yl)methoxy)-6-nitroquinazolin-4-amine(500 mg, 986 umol, 97% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ=10.07 (s, 1H), 9.21 (s, 1H), 8.64-8.59 (m, 2H), 8.02 (d,J=2.4 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz, 1H), 7.70 (dd, J=2.4, 9.0 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7.38 (dd, J=5.2, 6.6 Hz, 1H),7.29 (d, J=9.2 Hz, 1H), 5.30 (s, 2H), 4.35-4.30 (m, 1H), 4.27-4.21 (m,1H), 3.93-3.84 (m, 1H), 3.41-3.36 (m, 1H), 3.30-3.26 (m, 1H), 2.83-2.74(m, 1H), 2.28 (s, 3H), 2.05-1.97 (m, 2H). MS (ESI) m/z 507.1 [M+H]⁺

The mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazetidin-2-yl)methoxy)-6-nitroquinazolin-4-amine(600 mg, 1.18 mmol, 1.00 eq), iron powder (200 mg, 3.58 mmol, 3.03 eq)and ammonium chloride (320 mg, 5.98 mmol, 5.05 eq) in methanol (10.0 mL)and water (5.00 mL) was stirred at 80° C. for 2 h. The mixture wasfiltered, the filtrate was concentrated to afford a residue. The residuewas triturated with water (20.0 mL). After filtration, the filter cakewas washed with water (10.0 mL), dried in vacuum to giveN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazetidin-2-yl)methoxy)quinazoline-4,6-diamine(530 mg, 1.11 mmol, 93% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ=9.28 (br s, 1H), 8.60 (br s, 1H), 8.33 (s,1H), 8.06 (br s, 1H), 7.89 (br t, J=7.2 Hz, 1H), 7.71 (br d, J=8.4 Hz,1H), 7.59 (br d, J=7.6 Hz, 1H), 7.43 (br s, 1H), 7.38 (br s, 1H), 7.23(br d, J=8.6 Hz, 1H), 7.09 (s, 1H), 5.30-5.21 (m, 4H), 4.16 (br d, J=3.6Hz, 2H), 3.49-3.40 (m, 2H), 2.84-2.75 (m, 1H), 2.32 (s, 3H), 2.11-2.01(m, 2H). MS (ESI) m/z 477.2 [M+H]⁺

To the mixture ofN4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylazetidin-2-yl)methoxy)quinazoline-4,6-diamine(200 mg, 419 umol, 1.00 eq) and triethylamine (128 mg, 1.26 mmol, 176uL, 3.02 eq) in dimethylformamide (4.00 mL) was added prop-2-enoylchloride (44.0 mg, 486 umol, 40.0 uL, 1.16 eq) at 0° C. The mixture wasstirred at 25° C. for 1 h. The mixture was filtered. The filtrate waspurified by pre-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um;mobile phase: [water (0.225% FA)-ACN]; B %: 5%-35%, 10 min) and (column:Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 35%-65%, 10 min) to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylazetidin-2-yl)methoxy)quinazolin-6-yl)acrylamide116 (25.7 mg, 48.5 umol, 11% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ=9.68 (br d, J=2.0 Hz, 2H), 8.79 (s, 1H),8.64-8.57 (m, 1H), 8.50 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.89 (dt,J=1.6, 7.6 Hz, 1H), 7.71 (dd, J=2.4, 9.2 Hz, 1H), 7.60 (d, J=7.8 Hz,1H), 7.38 (dd, J=5.2, 6.5 Hz, 1H), 7.30-7.23 (m, 2H), 6.64 (br dd,J=10.0, 17.2 Hz, 1H), 6.31 (dd, J=1.8, 17.2 Hz, 1H), 5.81 (dd, J=1.8,10.2 Hz, 1H), 5.29 (s, 2H), 4.27-4.14 (m, 2H), 3.47-3.39 (m, 1H), 3.29(br d, J=3.2 Hz, 1H), 2.81-2.73 (m, 1H), 2.28 (s, 3H), 2.08-1.97 (m,2H). MS (ESI) m/z 531.1 [M+H]⁺

Synthesis of tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate

To the mixture of 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid(1.00 g, 4.97 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was addedborane dimethyl sulfide complex (10.0 M, 1.99 mL, 4.00 eq) at 0° C. Themixture was stirred at 25° C. for 3 h. The reaction was quenched bymethanol (20.0 mL) and the mixture was concentrated to dryness to give aresidue. The residue was poured into water (40.0 mL) and extracted withethyl acetate (3×20.0 mL). The combined organic layers were washed withbrine (30.0 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to afford tert-butyl2-(hydroxymethyl)azetidine-1-carboxylate (910 mg, 4.86 mmol, 98% yield)as a light brown oil. 1H NMR (400 MHz, CDCl3) δ=4.45 (br s, 1H),3.94-3.85 (m, 1H), 3.84-3.69 (m, 4H), 2.24-2.13 (m, 1H), 2.01-1.89 (m,1H), 1.47 (s, 9H).

117: To a suspension of 1-fluoro-2-methyl-4-nitro-benzene (5.00 g, 32.2mmol, 1.00 eq), phenol (3.34 g, 35.5 mmol, 3.12 mL, 1.10 eq) inacetonitrile (50.0 mL) was added potassium carbonate (13.4 g, 96.7 mmol,3.00 eq). The mixture was stirred at 80° C. for 12 h. The mixture wasconcentrated, diluted with water (50.0 mL), extracted with ethyl acetate(3×50.0 mL), washed with saturated sodium carbonate (3×20.0 mL), driedover anhydrous sodium sulfate, filtered and concentrated to afford2-methyl-4-nitro-1-phenoxy-benzene (7.00 g, 30.5 mmol, 95% yield) as ayellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.23 (br d, 1=2.1 Hz, 1H), 8.05 (dd, J=2.4,9.0 Hz, 1H), 7.54-7.43 (m, 2H), 7.32-7.22 (m, 1H), 7.18-7.07 (m, 2H),6.84 (d, J=9.0 Hz, 1H), 2.37 (s, 3H).

To a suspension of 2-methyl-4-nitro-1-phenoxy-benzene (4.00 g, 17.5mmol, 1.00 eq) in methanol (30.0 mL) was added Pd/C (400 mg, 17.5 mmol,10% purity). The mixture was degassed under vacuum and then stirred at20° C. for 24 h under hydrogen (15 psi, balloon). The mixture wasfiltered, concentrated to afford 3-methyl-4-phenoxy-aniline (3.30 g,16.6 mmol, 95% yield) as brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ=7.30-7.23 (m, 2H), 6.98-6.92 (m, 1H),6.80-6.73 (m, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 6.42(dd, J=2.7, 8.4 Hz, 1H), 4.91 (s, 2H), 1.96 (s, 3H).

To a suspension of 4-chloro-7-fluoro-6-nitro-quinazoline (3.43 g, 15.1mmol, 1.00 eq) in isopropanol (30.0 mL) was added3-methyl-4-phenoxy-aniline (3.00 g, 15.1 mmol, 1.00 eq). The mixture wasstirred at 80° C. for 2 h. The mixture was concentrated to give aresidue. The residue was triturated with ethyl acetate (10.0 mL) to givea crude product. The crude product was diluted with saturated potassiumcarbonate (30.0 mL), extracted with ethyl acetate (3×30.0 mL), washedwith brine (3×20.0 mL), dried over anhydrous sodium sulfate, filteredand concentrated to afford7-fluoro-N-(3-methyl-4-phenoxy-phenyl)-6-nitro-quinazolin-4-amine (3.00g, 7.69 mmol, 51% yield) as a red solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.45 (br s, 1H), 9.60 (d, J=8.1 Hz, 1H),8.66 (s, 1H), 7.80 (d, J=12.6 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.66 (dd,J=2.5, 8.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.13-7.05 (m, 1H), 6.99 (d, J=8.7Hz, 1H), 6.95-6.88 (m, 2H), 2.20 (s, 3H) To a solution of7-fluoro-N-(3-methyl-4-phenoxyphenyl)-6-nitroquinazolin-4-amine (3.00 g,7.69 mmol, 1.00 eq) in dimethylformamide (30.0 mL) was added potassiumacetate (3.77 g, 38.4 mmol, 5.00 eq) at 15° C. The mixture was stirredat 100° C. for 3 h. The mixture was concentrated to afford a residue.The residue was diluted with water (30.0 mL). After filtration, thefilter cake was washed with water (10.0 mL), dried in vacuum to afford4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-ol (2.80 g,crude) as a yellow solid.

MS (ESI) m/z 389.2 [M+H]⁺

To a solution of4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-ol (2.80 g, 7.20mmol, 1.00 eq) and pyridine (2.85 g, 36.0 mmol, 2.90 mL, 5.00 eq) indichloromethane (90.0 mL) was added triflic anhydride (4.06 g, 14.4mmol, 2.37 mL, 2.00 eq) slowly at 0° C. The mixture was stirred at 25°C. for 2 h. The mixture was concentrated to afford a residue. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=1/0-8/1) to afford4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (1.23 g, crude) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.76 (d, J=2.6 Hz, 1H), 8.76 (d, J=3.2 Hz,1H), 8.02 (br d, J=7.0 Hz, 1H), 7.73 (s, 1H), 7.67 (dd, J=2.3, 8.7 Hz,1H), 7.45-7.32 (m, 2H), 7.13-7.05 (m, 1H), 7.00 (dd, J=2.1, 8.7 Hz, 1H),6.94 (br d, J=8.6 Hz, 2H), 2.22 (s, 3H).

To a solution of tert-butyl6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (438 mg, 2.11 mmol,1.10 eq), 4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (1.00 g, 1.92 mmol, 1.00 eq), copper iodide(73.2 mg, 384 umol, 0.200 eq) and triethylamine (13.0 g, 128 mmol, 17.8mL, 66.6 eq) in dimethylformamide (20.0 mL) was addedtetrakis[triphenylphosphine] palladium(0) (222 mg, 192 umol, 0.100 eq)at 25° C.

The mixture was stirred at 25° C. for 3 h. The reaction was concentratedto afford a residue. The residue was triturated with ethyl acetate (10.0mL). After filtration, the filter cake was dried in vacuum to affordcrude product. The crude product was purified by silica gelchromatography (petroleum ether/ethyl acetate=5/1 to 2/1) to afford(1R,5S,6s)-tert-butyl6-((4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(950 mg, crude) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.29 (br s, 1H), 9.40 (s, 1H), 8.63 (s,1H), 7.85 (s, 1H), 7.77-7.44 (m, 2H), 7.33 (br t, J=7.4 Hz, 2H),7.07-7.00 (m, 1H), 6.94 (br d, J=8.6 Hz, 1H), 6.88 (br d, J=8.1 Hz, 2H),3.53 (br d, J=10.6 Hz, 2H), 3.40-3.33 (m, 2H), 2.16 (s, 3H), 2.06 (br s,2H), 1.44 (br s, 1H), 1.36 (s, 9H).

A mixture of (1R,5S,6s)-tert-butyl6-((4-((3-methyl-4-phenoxyphenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(890 mg, 1.54 mmol, 1.00 eq) in 4 M hydrochloride/ethyl acetate (7.00mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated toafford crude product. The crude product was purified by reversed phase(C18, 0.1% hydrochloric acid in water-acetonitrile) and lyophilized toafford7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-methyl-4-phenoxyphenyl)-6-nitroquinazolin-4-amine(600 mg, crude) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.27 (br s, 1H), 9.37 (s, 1H), 8.61 (s,1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.62 (dd,J=2.3, 8.6 Hz, 1H), 7.34-7.26 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 6.92 (d,J=8.7 Hz, 1H), 6.86 (dd, J=0.9, 8.6 Hz, 2H), 2.92 (d, J=11.7 Hz, 2H),2.68 (br d, J=11.2 Hz, 2H), 2.13 (s, 3H), 1.86 (br s, 2H), 1.56 (t,J=3.3 Hz, 1H).

To a solution of7-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylethynyl)-N-(3-methyl-4-phenoxyphenyl)-6-nitroquinazolin-4-amine(400 mg, 837 umol, 1.00 eq) and paraformaldehyde (126 mg, 4.19 mmol, 115uL, 5.00 eq) in trifluoroethanol (11.0 mL) was added sodium borohydride(63.4 mg, 1.68 mmol, 2.00 eq) at 60° C. The mixture was stirred at 60°C. for 12 h.

The mixture was concentrated to afford a residue. The residue wasdiluted with saturated sodium carbonate (3.00 mL) and water (10.0 mL),extracted with ethyl acetate (3×20.0 mL). The combined organic layer waswashed with water (20.0 mL), dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated to afford7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N-(3-methyl-4-phenoxyphenyl)-6-nitroquinazolin-4-amine(400 mg, crude) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=10.33 (br s, 1H), 9.44 (s, 1H), 8.68 (s,1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.68 (dd, J=2.2, 8.6 Hz, 1H), 7.43-7.36(m, 2H), 7.13-7.07 (m, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.93 (d, J=7.8 Hz,2H), 3.03 (d, J=9.2 Hz, 2H), 2.34-2.29 (m, 2H), 2.24 (s, 3H), 2.21 (s,3H), 2.00-1.90 (m, 3H).

To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N-(3-methyl-4-phenoxyphenyl)-6-nitroquinazolin-4-amine(350 mg, 712 umol, 1.00 eq) and ammonium chloride (430 mg, 8.05 mmol,134 uL, 11.3 eq) in methanol (20.0 mL) and water (20.0 mL) was addediron powder (537 mg, 9.61 mmol, 13.5 eq) at 25° C. The mixture washeated to 80° C. and stirred at 80° C. for 1 h. The mixture wasconcentrated to afford a residue. The residue was diluted with water(20.0 mL), saturated sodium carbonate (1.00 mL), ethyl acetate (50.0mL). The mixture was extracted with ethyl acetate (2×30.0 mL) and thecombined organic layer was washed with water (10.0 mL), dried overanhydrous sodium sulfate, filtered. The filtrate was concentrated toafford7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N-(3-methyl-4-phenoxyphenyl)quinazoline-4,6-diamine(200 mg, crude) as a brown solid.

MS (ESI) m/z 462.3 [M+H]⁺

To a solution of7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-N⁴-(3-methyl-4-phenoxyphenyl)quinazoline-4,6-diamine(200 mg, 433 umol, 1.00 eq) and pyridine (0.500 M in dimethylformamide,4.33 mL, 5.00 eq) in dimethylformamide (4.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (831 mg,4.33 mmol, 10.0 eq) and acrylic acid (0.500 M in dimethylformamide, 4.33mL, 5.00 eq, 2.41 mL, 1.20 eq) at 0° C. The mixture was stirred at 25°C. for 1 h. The mixture was filtered to afford a solution. The solutionwas purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B %: 62%-82%,10 min) and lyophilized to affordN-(7-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-4-((3-methyl-4-phenoxyphenyl)amino)quinazolin-6-yl)acrylamide(25.6 mg, 49.7 umol, 11% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.85 (d, J=3.9 Hz, 2H), 8.74 (s, 1H), 8.54(s, 1H), 7.81-7.73 (m, 2H), 7.69 (dd, J=2.5, 8.5 Hz, 1H), 7.40-7.33 (m,2H), 7.07 (t, J=7.3 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.94-6.89 (m, 2H),6.64 (dd, J=10.2, 16.9 Hz, 1H), 6.34 (dd, J=1.8, 17.0 Hz, 1H), 5.86 (dd,J=1.8, 10.2 Hz, 1H), 3.02 (d, J=9.2 Hz, 2H), 2.31 (br d, J=8.6 Hz, 2H),2.25 (s, 3H), 2.19 (s, 3H), 1.94 (br s, 2H), 1.92-1.89 (m, 1H). MS (ESI)m/z 516.3 [M+H]⁺

118: Synthesized according to general procedure B, wherein in step B.1propane-1,3-diol was used; in step B.2 variant ii) was used, in step B.3the nucleophile is 3-methoxyazetidine, in step B.4 variant ii) was usedand variant i) was used in step B.5; and 6% overall yield from III. ¹HNMR (400M Hz, DMSO-d₆) δ=9.67 (s, 1H), 9.58 (s, 1H), 8.84 (s, 1H), 8.60(d, J=4.5 Hz, 1H), 8.48 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.88 (dt,J=1.8, 7.7 Hz, 1H), 7.69 (dd, J=2.6, 8.9 Hz, 1H), 7.59 (d, J=7.8 Hz,1H), 7.37 (dd, J=5.1, 7.1 Hz, 1H), 7.26 (s, 1H), 7.23 (s, 1H), 6.71 (brdd, J=10.2, 16.9 Hz, 1H), 6.31 (dd, J=1.8, 17.1 Hz, 1H), 5.88-5.75 (m,1H), 5.28 (s, 2H), 4.21 (br t, J=6.3 Hz, 2H), 4.01-3.87 (m, 1H), 3.94(quin, J=5.8 Hz, 1H), 3.51 (br dd, J=6.1, 7.9 Hz, 2H), 3.14 (s, 3H),2.77 (dd, J=5.9, 7.8 Hz, 3H), 2.60-2.55 (m, 1H), 2.60-2.55 (m, 1H),2.60-2.55 (m, 4H), 1.83 (quin, J=6.5 Hz, 2H). MS (ESI) m/z 575.4 [M+H]⁺119: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine(1.00 g, 2.06 mmol, 1.00 eq) (obtained from general procedure B [IX]),tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (652 mg, 2.26 mmol,1.10 eq, oxalic acid), potassium carbonate (1.14 g, 8.23 mmol, 4.00 eq)and potassium iodide (341 mg, 2.06 mmol, 1.00 eq) in acetonitrile (10.0mL) was stirred at 110° C. for 12 h. The reaction was concentrated togive a residue. The residue was triturated with water (50.0 mL) to givetert-butyl6-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.20 g, crude) as a yellow solid. MS (ESI) m/z 648.3 [M+H]⁺

A mixture oftert-butyl-(4-(4-((3-chloro-2-fluorophenyl)amino)-6-nitroquinazolin-7-yl)-2-methylbut-3-yn-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.00 g, 1.54 mmol, 1.00 eq), iron (861 mg, 15.4 mmol, 10.0 eq) andammonium chloride (825 mg, 15.4 mmol, 10.0 eq) in methanol (10.0 mL) andwater (10.0 mL) was stirred at 80° C. for 1 h. The reaction mixture wasconcentrated to give a residue. The residue was purified byreversed-phase HPLC (0.1% NH₃.H₂O) and lyophilized to give tert-butyl6-(4-(6-amino-4-((3-chloro-2-fluorophenyl)amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(500 mg, 808 umol, 52% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.61 (d, J=4.6 Hz, 1H), 8.57 (s, 1H), 7.85 (d, J=2.4 Hz, 1H),7.80-7.73 (m, 1H), 7.71-7.64 (m, 1H), 7.49 (dd, J=2.5, 8.9 Hz, 1H), 7.26(br d, J=7.0 Hz, 1H), 7.16 (s, 1H), 7.07-6.98 (m, 2H), 6.94 (s, 1H),5.31 (s, 2H), 4.18 (t, J=5.3 Hz, 2H), 4.02 (s, 4H), 3.48 (s, 4H), 2.93(t, J=5.2 Hz, 2H), 1.45 (s, 9H).

To a solution of tert-butyl6-(4-(6-amino-4-((3-chloro-2-fluorophenyl)amino)quinazolin-7-yl)-2-methylbut-3-yn-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(200 mg, 323 umol, 1.00 eq) and triethylamine (65.5 mg, 647 umol, 2.00eq) in dimethyl formamide (2.00 mL) was added acrylic anhydride (40.8mg, 323 umol, 1.00 eq) at 25° C. The mixture was stirred at 25° C. for0.5 h.

The reaction mixture was quenched by addition water (10.0 mL) andextracted with ethyl acetate (3/30.0 mL). The combined organic layerswere washed with brine (3×10.0 mL), dried over sodium sulfate, filteredand concentrated under reduced pressure to give tert-butyl6-(2-((6-acrylamido-4-((3-chloro-4-(pyridine-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (210 mg, crude) as ayellow solid. MS (ESI) m/z 672.3 [M+H]⁺

A mixture of tert-butyl6-(2-((6-acrylamido-4-((3-chloro-4-(pyridine-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 297 umol, 1.00eq) and trifluoroacetic acid (616 mg, 5.40 mmol, 400 uL, 18.2 eq) indichloromethane (2.00 mL) was stirred at 25° C. for 0.5 h. The residuewas triturated with ethyl acetate (5.00 mL) and ethyl acetate (20.0 mL)to giveN-(7-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(200 mg, crude) as a yellow solid.

MS (ESI) m/z 572.3 [M+H]⁺

To a mixture ofN-(7-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-4-((3-chloro-4-(pyridine-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(100 mg, 174 umol, 1.00 eq) and formaldehyde (26.2 mg, 874 umol, 5.00eq) in 2,2,2-trifluoroethanol (1.00 mL) was added sodium borohydride(13.2 mg, 349 umol, 2.00 eq) at 40° C. The mixture was stirred at 40° C.for 0.5 h. The reaction mixture was concentrated to give a residue. Theresidue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 um;mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN]; B %: 50%-83%,10 min) and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)quinazolin-6-yl)acrylamide 119 (5.95 mg, 10.2 umol, 5.8% yield,100% purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=9.12 (s, 1H),9.06 (s, 1H), 8.64 (s, 1H), 8.62 (br d, J=4.8 Hz, 1H), 7.91 (d, J=2.6Hz, 1H), 7.80-7.75 (m, 1H), 7.70-7.64 (m, 2H), 7.53 (dd, J=2.6, 8.9 Hz,1H), 7.26 (s, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.58-6.37 (m, 2H), 5.86 (dd,J=2.5, 9.0 Hz, 1H), 5.32 (s, 2H), 4.19 (t, J=5.1 Hz, 2H), 3.44 (s, 4H),3.32 (s, 4H), 2.93 (t, 0.1=5.1 Hz, 2H), 2.30 (s, 3H). MS (ESI) m/z 586.3[M+H]⁺

120: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(1.00 g, 2.35 mmol, 1.00 eq) (obtained from general procedure A [III])in dimethylsulfoxide (10.0 mL) was added tert-butyl3-(2-hydroxyethyl)morpholine-4-carboxylate (815 mg, 3.52 mmol, 1.50 eq)and potassium tert-butoxide (790 mg, 7.05 mmol, 3.00 eq) at 30° C. Themixture was stirred at 30° C. for 3 h. The mixture was diluted withwater (90.0 mL) and some solid was precipitated out. Filtered and thefilter cake was dried to give tert-butyl3-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)morpholine-4-carboxylate(1.20 g, 1.80 mmol, 76% yield, 95% purity) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=10.06 (br s, 1H), 9.20 (br s, 1H), 8.60 (br s, 2H),8.08-7.82 (m, 2H), 7.76-7.51 (m, 2H), 7.38 (br s, 2H), 7.27 (br d, J=8.4Hz, 1H), 5.29 (br s, 2H), 4.30 (br s, 2H), 4.10 (br d, J=4.0 Hz, 5H),3.77 (br d, J=9.2 Hz, 2H), 3.62 (br s, 1H), 3.48 (br d, J=11.2 Hz, 2H),2.36-2.20 (m, 1H), 2.08 (br s, 1H), 1.23 (br s, 9H). MS (ESI) m/z 637.0[M+H]⁺

A solution of tert-butyl3-(2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)ethyl)morpholine-4-carboxylate(1.20 g, 1.80 mmol, 1.00 eq) in dioxane hydrochloride (4.00 M, 450 uL,1.00 eq) was stirred at 30° C. for 1 h. The mixture was concentrated invacuo to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(morpholin-3-yl)ethoxy)quinazoline-4,6-diamine(1.00 g, 1.67 mmol, 92% yield, 95% purity, hydrochloride) as a whitesolid. MS (ESI) m/z 537.0 [M+H]⁺

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(morpholin-3-yl)ethoxy)quinazoline-4,6-diamine(1.00 g, 1.74 mmol, 1.00 eq, hydrochloride) in dichloromethane (10.0 mL)and methanol (10.0 mL) was added formaldehyde (184 mg, 2.27 mmol, 3.27uL, 37% purity, 1.30 eq) and sodium borohydride acetate (554 mg, 2.62mmol, 1.50 eq) at 30° C. The mixture was stirred at 30° C. for 18 h. Themixture was diluted with saturated sodium bicarbonate (30.0 mL), andthen extracted with dichloromethane (3×50.0 mL). The combined organicphase was washed with brine (30.0 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylmorpholin-3-yl)ethoxy)-6-nitroquinazolin-4-amine(900 mg, 1.62 mmol, 92% yield, 99% purity) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=10.22 (br s, 1H), 9.29 (s, 1H), 8.66-8.55 (m, 2H),8.03 (d, J=2.4 Hz, 1H), 7.89 (dt, J=1.6, 7.7 Hz, 1H), 7.71 (dd, J=2.4,9.1 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J=5.2, 6.8Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 5.30 (s, 2H), 4.38-4.30 (m, 2H), 4.23(d, J=9.2 Hz, 1H), 4.12 (q, J=5.2 Hz, 1H), 4.02 (d, 0.1=9.2 Hz, 1H),3.78-3.70 (m, 1H), 3.70-3.60 (m, 1H), 3.55-3.44 (m, 1H), 3.20-3.15 (m,4H), 2.96-2.70 (m, 2H). MS (ESI) m/z 550.1 [M+H]⁺

To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylmorpholin-3-yl)ethoxy)-6-nitroquinazolin-4-amine(900 mg, 1.63 mmol, 1.00 eq) in methanol (1.00 mL) and water (1.00 mL)was added iron powder (456 mg, 8.17 mmol, 5.00 eq) and ammonium chloride(437 mg, 8.17 mmol, 5.00 eq) at 30° C. The mixture was stirred at 80° C.for 5 h. The mixture was diluted with saturated sodium bicarbonatesolution (50.0 mL), and then extracted with ethyl acetate (2×50.0 mL).The combined organic phase was washed with brine (50.0 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to giveN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylmorpholin-3-yl)ethoxy)quinazoline-4,6-diamine (600 mg, 1.15 mmol, 70% yield, 100% purity) as ayellow solid. MS (ESI) m/z 521.3 [M+H]⁺

To a solution of acrylic acid (49.8 mg, 691 umol, 47.4 uL, 1.20 eq) indimethyl formamide (2.00 mL) was addedN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(2-(4-methylmorpholin-3-yl)ethoxy)quinazoline-4,6-diamine(300 mg, 575 umol, 1.00 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (441 mg,2.30 mmol, 4.00 eq) and pyridine (182 mg, 2.30 mmol, 186 uL, 4.00 eq) at30° C. The mixture was stirred at 30° C. for 1 h. The mixture wasconcentrated in vacuo to give the crude product. The crude product waspurified by prep-HPLC (water (10 mM ammonium bicarbonate)-acetonitrile];B %: 37%-57%, 10 min) to give a yellow solid which was further purifiedby prep-HPLC (0.05% ammonia hydroxide v/v)-acetonitrile]; B %: 30%-60%,10 min) to give N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(2-(4-methylmorpholin-3-yl)ethoxy)quinazolin-6-yl)acrylamide120 (36.52 mg, 63.51 umol, 11% yield, 100% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ=9.10 (s, 1H), 8.64 (s, 1H), 8.61 (d, J=5.2 Hz,1H), 8.34 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.80-7.73 (m, 2H), 7.70-7.65(m, 1H), 7.56-7.51 (m, 1H), 7.26-7.23 (m, 2H), 7.02 (d, J=8.8 Hz, 1H),6.55-6.47 (m, 1H), 6.39-6.28 (m, 1H), 5.88 (d, J=11.2 Hz, 1H), 5.31 (s,2H), 4.39-4.20 (m, 2H), 3.88-3.79 (m, 2H), 3.76-3.66 (m, 1H), 3.53 (dd,J=8.8, 11.2 Hz, 1H), 2.78 (td, J=3.2, 11.9 Hz, 1H), 2.49-2.40 (m, 2H),2.39 (s, 3H), 2.21-2.06 (m, 2H). MS (ESI) m/z 575.3 [M+H]⁺

121: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 2-(4-amino-2-chlorophenyl)-1-(pyridin-2-yl)ethanone: in stepA.3 the NH nucleophile is (R)-1-methylpyrrolidin-3-ol; variant ii) wasused in step A.4, and variant iii) was used in step A.5; and 3% overallyield from II. ¹H NMR (400 MHz, CDCl₃) δ=9.15 (s, 1H), 8.87 (br s, 1H),8.77 (br d, J=4.8 Hz, 1H), 8.68 (s, 1H), 8.15-8.09 (m, 1H), 8.06 (d,J=2.0 Hz, 1H), 7.91-7.85 (m, 2H), 7.64 (dd, 1=8.4, 2.2 Hz, 1H), 7.54(dd, J=7.0, 5.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 6.51 (brd, J=4.6 Hz, 2H), 5.90-5.81 (m, 1H), 5.10 (br s, 1H), 4.74 (s, 2H),3.29-3.09 (m, 2H), 2.70 (br d, J=6.4 Hz, 1H), 2.60-2.52 (m, 1H), 2.50(s, 3H), 2.45-2.37 (m, 1H), 2.24-2.12 (m, 1H). MS (ESI) m/z 543.2 [M+H]⁺

Synthesis of 2-(4-amino-2-chlorophenyl)-1-(pyridin-2-yl)ethanone

To a solution of 1-(pyridin-2-yl)ethanone (5.00 g, 41.3 mmol, 1.00 eq)and 1-chloro-3-nitrobenzene (13.0 g, 82.5 mmol, 2.00 eq) indimethylsulfoxide (100 mL) was added sodium tert-butoxide (4.76 g, 49.5mmol, 1.20 eq) at 25° C. The mixture was stirred at 25° C. for 1 h.

The reaction mixture was diluted with water (50.0 mL) and extracted withethyl acetate (3×50.0 mL). The combined organic layers were washed withbrine (50.0 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 3/1)to give 2-(2-chloro-4-nitrophenyl)-1-(pyridin-2-yl)ethanone (3.50 g,10.5 mmol, 25% yield, 83% purity) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ=8.71-8.64 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.07-7.99 (m, 2H),7.82 (dt, J=1.6, 7.6 Hz, 1H), 7.48 (ddd, J=1.0, 4.8, 7.6 Hz, 1H), 7.41(d, J=8.4 Hz, 1H). MS (ESI) m/z 277.1 [M+H]⁺

To a solution of 2-(2-chloro-4-nitrophenyl)-1-(pyridin-2-yl)ethanone(500 mg, 1.50 mmol, 1.00 eq) in ethyl alcohol (10.0 mL) and hydrochloricacid (10.0 mL) was added dihydrate tin chloride (1.35 g, 6.00 mmol, 4.00eq) at 25° C. The mixture was stirred at 50° C. for 1 h. The reactionmixture was diluted with water (20.0 mL) and to the mixture was addedsodium carbonate to pH=8˜9. Then it was extracted with ethyl acetate(3×50.0 mL). The combined organic layers were concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give2-(4-amino-2-chlorophenyl)-1-(pyridin-2-yl)ethanone (200 mg, 405 umol,27% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.87-8.64 (m,1H), 8.20-8.00 (m, 1H), 7.87 (dt, J=1.6, 7.6 Hz, 1H), 7.51 (ddd, J=1.2,4.8, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.59(dd, J=2.4, 8.0 Hz, 1H), 4.62 (s, 2H). MS (ESI) m/z 247.1 [M+H]⁺

122: A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(230 mg, 1.01 mmol, 1.00 eq) (obtained via general procedure A [III]),tert-butyl 1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate(0.430 g, 1.01 mmol, 1.00 eq) and potassium tert-butoxide (227 mg, 2.02mmol, 2.00 eq) in dimethylsulfoxide (10.0 mL) was stirred at 25° C. for2 h. The reaction mixture was diluted with water (15.0 mL) and extractedwith ethyl acetate (3×50.0 mL). The combined organic layers were washedwith brine (20.0 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford tert-butyl1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate(0.600 g, crude) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=9.41 (brs, 1H), 9.25 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H),7.78-7.77 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.56 (s, 1H), 7.53-7.51 (m,1H), 7.18 (br s, 1H), 6.93-6.90 (m, 1H), 5.22 (s, 2H), 4.73 (s, 2H),3.84 (br d, J=5.0 Hz, 1H), 1.77 (br d, J=3.9 Hz, 4H), 1.71-1.65 (m, 4H),1.38 (s, 9H).

A mixture of tert-butyl1-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (0.700 g, 1.11mmol, 1.00 eq) in hydrochloric acid/ethyl acetate (10.0 mL) was stirredat 25° C. for 0.5 h. The reaction mixture was concentrated under reducedpressure to afford7-(7-azabicyclo[2.2.1]heptan-1-ylmethoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine (0.7 g, crude, hydrochloride) as ayellow solid.

MS (ESI) m/z 533.3 [M+H]⁺

To a solution of7-(7-azabicyclo[2.2.1]heptan-1-ylmethoxy)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine(0.700 g, 1.23 mmol, 1.00 eq, hydrochloride) and paraformaldehyde (185mg, 6.15 mmol, 169 uL, 5.00 eq) in trifluoroethanol (10.0 mL) was addedsodium borohydride (93.0 mg, 2.46 mmol, 2.00 eq). The mixture wasstirred at 60° C. for 12 h. The reaction mixture was concentrated underreduced pressure to give a residue. The residue was purified by reversedphase chromatography (column: C18, 80 g; condition: H₂O-0.1%NH₃H₂O—CH₃CN) and lyophilized to affordN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)-6-nitroquinazolin-4-amine(0.200 g, 366 umol, 30% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ=8.60 (s, 1H), 8.50-8.46 (m, 1H), 8.43 (s, 1H), 7.73 (d, J=2.6Hz, 1H), 7.68-7.62 (m, 1H), 7.56-7.46 (m, 2H), 7.34 (dd, J=2.7, 8.8 Hz,1H), 7.29 (s, 1H), 7.12 (br s, 1H), 6.90 (d, J=8.9 Hz, 1H), 5.18 (s,2H), 4.27 (s, 2H), 3.20-3.13 (m, 1H), 2.16 (s, 3H), 1.87-1.71 (m, 4H),1.46-1.41 (m, 2H), 1.37-1.29 (m, 2H).

A mixture ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)-6-nitroquinazolin-4-amine (0.200 g, 366 umol, 1.00 eq),ammonium chloride (58.7 mg, 1.10 mmol, 3.00 eq) and ferrous powder (61.3mg, 1.10 mmol, 3.00 eq) in a mixture solvent of methanol (3.00 mL) andwater (3.00 mL) was stirred at 80° C. for 5 h. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified was by reversed phase chromatography (column: C18,80 g; condition: H₂O-0.1% NH₃.H₂O—CH₃CN) and lyophilized to affordN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)quinazoline-4,6-diamine(150 mg, 290 umol, 79% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ=8.47 (d, J=4.5 Hz, 1H), 8.43 (s, 1H), 7.72 (d,J=2.7 Hz, 1H), 7.66-7.59 (m, 1H), 7.56-7.51 (m, 1H), 7.35 (dd, J=2.6,8.9 Hz, 1H), 7.12-7.09 (m, 1H), 7.08 (s, 1H), 6.88 (d, J=8.9 Hz, 1H),6.78 (s, 1H), 6.76 (s, 1H), 5.17 (s, 2H), 4.35 (br s, 2H), 4.17 (s, 2H),3.24-3.19 (m, 1H), 2.14 (s, 3H), 1.86-1.73 (m, 4H), 1.44-1.32 (m, 4H).

A mixture ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)quinazoline-4,6-diamine (0.150 g, 290 umol, 1.00 eq), acrylicacid (41.8 mg, 580 umol, 39.8 uL, 2.00 eq),1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (167 mg,870 umol, 3.00 eq) and pyridine (68.9 mg, 870 umol, 70.3 uL, 3.00 eq) indimethylformamide (2.00 mL) was stirred at 25° C. for 10 h. The reactionmixture was extracted with ethyl acetate (3-35.0 mL). The combinedorganic layers were washed with brine (15.0 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure to givea residue. The residue was purified by prep-HPLC (column: Xtimate C18150×25 mm×5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN];B %: 47%-77%, 10 min) and lyophilized to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)quinazolin-6-yl)acrylamide122 (37.02 mg, 64.2 umol, 31% yield, 99% purity) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ=9.82 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 8.61(br d, 1=4.8 Hz, 1H), 7.96-7.82 (m, 2H), 7.81-7.73 (m, 1H), 7.68 (d,J=7.8 Hz, 1H), 7.53 (dd, J=2.6, 8.9 Hz, 1H), 7.28-7.24 (m, 1H), 6.99 (d,J=8.9 Hz, 1H), 6.74-6.62 (m, 1H), 6.53-6.42 (m, 1H), 5.76 (dd, 1=1.4,10.2 Hz, 1H), 5.30 (s, 2H), 4.29 (s, 2H), 3.46-3.32 (m, 1H), 2.24 (s,3H), 1.99 (br s, 4H), 1.53 (br d, J=7.3 Hz, 4H). MS (ESI) m/z 571.4[M+H]⁺

Synthesis of tert-butyl1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To a solution of tert-butyl1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate (0.300 g, 1.33 mmol,1.00 eq) in methanol (2.00 mL) was added sodium borohydride (60.5 mg,1.60 mmol, 1.20 eq) slowly. The mixture was stirred at 0° C. for 1 h.The reaction mixture was quenched by saturated aqueous solution ofsodium bicarbonate (5.00 mL) and extracted with ethyl acetate (3×30.0mL). The combined organic layers were washed with brine (10 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford tert-butyl1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (290 mg, 1.28mmol, 96% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=4.17 (t,J=4.7 Hz, 1H), 3.84 (d, J=7.1 Hz, 2H), 1.84-1.75 (m, 2H), 1.74-1.67 (m,2H), 1.43-1.39 (m, 1H), 1.38 (s, 9H), 1.36-1.28 (m, 3H).

123: To a solution ofN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-fluoro-6-nitroquinazolin-4-amine(0.500 g, 1.17 mmol, 1.00 eq) (obtained via general procedure A [III])and tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (263 mg, 1.41mmol, 1.20 eq) in dimethyl sulfoxide (10.0 mL) was added potassiumtert-butoxide (527 mg, 4.70 mmol, 4.00 eq) in portions at 25° C. Themixture was stirred at 25° C. for 2 h. The reaction mixture was dilutedwith water (100 mL) and filtered. Then the filter cake was dried to givetert-butyl3-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(480 mg, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.09 (brs, 1H), 9.22 (s, 1H), 8.68-8.51 (m, 2H), 8.01 (d, J=2.0 Hz, 1H),7.94-7.84 (m, 1H), 7.70 (dd, J=2.0, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H),7.48 (s, 1H), 7.38 (dd, J=5.2, 6.8 Hz, 1H), 7.29 (d, J=9.2 Hz, 1H), 5.30(s, 2H), 4.43 (br d, J=6.0 Hz, 2H), 3.96 (br s, 2H), 3.77 (br s, 2H),3.11-2.97 (m, 1H), 1.40 (s, 9H). MS (ESI) m/z 593.2 [M+H]⁺

The mixture of tert-butyl3-(((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate (300 mg, 506 umol, 1.00 eq), ironpowder (113 mg, 2.02 mmol, 4.00 eq) and ammonium chloride (140 mg, 2.62mmol, 5.17 eq) in methanol (10.0 mL) and water (5.00 mL) was stirred at80° C. for 2 h. The mixture was filtered, the filtrate was concentratedto afford a residue. The residue was triturated with water (20.0 mL).After filtration, the filter cake was washed with water (10.0 mL), driedin vacuum to give tert-butyl3-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate (280 mg, 497 umol,98% yield) as a brown solid. MS (ESI) m/z 563.4 [M+H]⁺

To the mixture of tert-butyl3-(((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(200 mg, 355 umol, 1.00 eq) and triethylamine (109 mg, 1.08 mmol, 150uL, 3.04 eq) in tetrahydrofuran (3.00 mL) was added acrylic anhydride(90.0 mg, 714 umol, 2.01 eq) at 25° C. The mixture was stirred at 25° C.for 2 h. The reaction mixture was poured into water (20.0 mL) andextracted with ethyl acetate (3×10.0 mL). The combined organic layerswere washed with brine (10.0 mL), dried over anhydrous sodium sulfate,filtered and concentrated to afford a residue. The residue was purifiedby prep-TLC (methanol/dichloromethane=10/1) to afford tert-butyl3-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(85.0 mg, 138 umol, 39% yield) as a brown solid. ¹H NMR (400 MHz, DMSO₆)δ=9.70 (s, 1H), 9.55 (s, 1H), 8.83 (s, 1H), 8.61 (d, J=4.4 Hz, 1H), 8.50(s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.89 (dt, J=1.6, 7.6 Hz, 1H), 7.70 (dd,J=2.4, 9.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.38 (dd, J=5.2, 7.2 Hz,1H), 7.32 (s, 1H), 7.26 (d, J=9.2 Hz, 1H), 6.66 (dd, J=10.4, 17.2 Hz,1H), 6.31 (dd, J=1.6, 17.2 Hz, 1H), 5.85-5.77 (m, 1H), 5.29 (s, 2H),4.37 (d, J=6.4 Hz, 2H), 3.98 (br s, 2H), 3.77 (br s, 2H), 3.10-3.02 (m,1H), 1.39 (s, 9H). MS (ESI) m/z 617.3 [M+H]⁺

To the mixture of tert-butyl3-(((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)oxy)methyl)azetidine-1-carboxylate(50.0 mg, 81.0 umol, 1.00 eq) in dichloromethane (1.00 mL) was addedtrifluoroacetic acid (508 mg, 4.46 mmol, 330 uL, 55.0 eq) at 25° C. Themixture was stirred at 25° C. for 0.5 h. The mixture was concentrated todryness to giveN-(7-(azetidin-3-ylmethoxy)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(50.0 mg, crude) as a brown solid which was used to next step withoutpurification. MS (ESI) m/z 517.3 [M+H]⁺

To the mixture ofN-(7-(azetidin-3-ylmethoxy)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(50.0 mg, 96.7 umol, 1.00 eq) and paraformaldehyde (15.0 mg, 500 umol,13.8 uL, 5.17 eq) in trifluoroethanol (1.00 mL) was added sodiumborohydride (8.00 mg, 211 umol, 2.19 eq) at 25° C. The mixture wasstirred at 60° C. for 1 h and quenched by saturated ammonium chloridesolution (1.00 mL). The mixture was purified by prep-HPLC (column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−ACN]; B %: 50%/6-80%, 10 min) to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((1-methylazetidin-3-yl)methoxy)quinazolin-6-yl)Acrylamide 123 (14.9 mg, 27.8 umol, 29% yield, 99% purity) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.67 (br d, J=15.2 Hz, 2H), 8.84 (s, 1H),8.60 (d, J=4.0 Hz, 1H), 8.48 (br s, 1H), 7.99 (br d, J=2.0 Hz, 1H), 7.89(dt, J=1.6, 7.6 Hz, 1H), 7.69 (br d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz,1H), 7.38 (dd, J=5.2, 6.5 Hz, 1H), 7.29-7.22 (m, 2H), 6.65 (br dd,J=10.4, 17.1 Hz, 1H), 6.32 (dd, J=1.6, 17.0 Hz, 1H), 5.86-5.79 (m, 1H),5.29 (s, 2H), 4.32 (d, J=6.0 Hz, 2H), 3.30-3.27 (m, 2H), 3.07 (t, J=6.4Hz, 2H), 2.89-2.82 (m, 1H), 2.22 (s, 3H). MS (ESI) m/z 531.3 [M+H]

124: To a solution of(4-(3-chloro-4-(2-pyridylmethoxy)aniline)-6-nitro-quinazolin-7-yl)trifluoromethanesulfonate (2.00 g, 3.60 mmol, 1.00 eq) (obtained bytriflation of the corresponding alcohol), tert-butyl6-ethynyl-2-azaspiro[3.3]heptanes-2-carboxylate (876 mg, 3.96 mmol, 1.10eq), copper(I) iodide (137 mg, 719 umol, 0.200 eq) and triethylamine(2.91 g, 28.8 mmol, 4.00 mL, 7.99 eq) in dimethyl formamide (4.00 mL)was added tetrakis(triphenylphosphine)palladium(0) (420 mg, 363 umol,0.370 eq) at 25° C. under nitrogen atmosphere, the mixture was stirredat 25° C. for 2 h. The reaction mixture was concentrated to give aresidue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=1/1-0/1) to affordtert-butyl-6-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(1.20 g, 1.91 mmol, 53% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=10.35 (s, 1H), 9.42 (s, 1H), 8.71 (s, 1H), 8.61 (br d, J=5.2Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.95 (s, 1H), 7.91-7.84 (m, 1H), 7.72(dd, J=2.2, 9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H),5.32 (s, 2H), 3.88 (br d, J=9.2 Hz, 4H), 3.17 (d, J=5.2 Hz, 1H), 2.33(br s, 4H), 1.38 (s, 9H). MS (ESI) m/z 627.5 [M+H]

The mixture of tert-butyl6-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(1.00 g, 1.59 mmol, 1.00 eq), iron powder (267 mg, 4.78 mmol, 3.00 eq),saturated ammonium chloride (426 mg, 7.97 mmol, 5.00 eq) in methanol(20.0 mL) and water (10.0 mL) was stirred at 80° C. for 1 h. Thereaction mixture was filtrated to give the filtrate, the filtrated waspoured into water (50.0 mL) and the aqueous phase was extracted withethyl acetate (4-50.0 mL). The combined organic phase was washed withbrine (30.0 mL), dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum to give a residue, the residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/1-0/1) toafford tert-butyl6-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(800 mg, 1.34 mmol, 84% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.52 (s, 1H), 8.68-8.63 (m, 1H), 8.38 (s,1H), 8.10 (d, J=2.6 Hz, 1H), 7.94 (dt, J=1.8, 7.8 Hz, 1H), 7.76 (dd,1=2.6, 8.8 Hz, 1H), 7.67-7.61 (m, 2H), 7.51 (s, 1H), 7.43 (dd, J=5.2,7.0 Hz, 1H), 7.30 (d, J=9.2 Hz, 1H), 5.64 (s, 2H), 5.34 (s, 2H),4.01-3.88 (m, 4H), 3.31 (br d, J=8.4 Hz, 1H), 2.68-2.59 (m, 4H), 1.43(s, 9H). MS (ESI) m/z 597.5 [M+H]

To a solution of tert-butyl6-((6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(500 mg, 837 umol, 1.00 eq), triethylamine (424 mg, 4.19 mmol, 583 uL,5.00 eq) in dimethyl formamide (5.00 mL) was added prop-2-enoylprop-2-enoate (316 mg, 2.51 mmol, 3.00 eq) at 25° C., the mixture wasstirred at 25° C. for 1 h. The reaction mixture was poured into water(50.0 mL) and extracted with ethyl acetate (3×40.0 mL). The combinedorganic phase was washed with brine (30.0 mL), dried with anhydroussodium sulfate, filtered and concentrated in vacuum to give a residue,the residue was purified by silica gel chromatography (petroleumether/ethyl acetate=2/1-0/1) to afford tert-butyl6-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(200 mg, 307 umol, 37% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.88 (d, J=13.6 Hz, 2H), 8.73-8.69 (m, 1H), 8.03-8.01 (m,1H), 7.92-7.87 (m, 1H), 7.79 (s, 1H), 7.72 (dd, J=2.6, 9.0 Hz, 1H), 7.59(d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.30-7.26 (m, 1H), 6.68-6.59 (m,1H), 6.38-6.32 (m, 1H), 5.88-5.84 (m, 1H), 5.32-5.29 (m, 2H), 3.87 (brd, J=19.8 Hz, 4H), 3.28-3.21 (m, 1H), 2.63-2.57 (m, 2H), 2.40-2.34 (m,2H), 1.38 (s, 9H). MS (ESI) m/z 651.4 [M+H]⁺

To a solution of tert-butyl6-((6-acrylamido-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-7-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate(40.0 mg, 61.4 umol, 1.00 eq) in dichloromethane (2.00 mL) was addedtrifluoroacetic acid (693 mg, 6.08 mmol, 450 uL, 99.0 eq) at 25° C., themixture was stirred at 25° C. for 0.5 h. The reaction mixture wasconcentrated to give a residue, the residue was poured into methanol(10.0 mL) and stirred, concentrated in vacuum to give crude productN-(7-(2-azaspiro[3.3]heptan-6-ylethynyl)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(40.0 mg, crude) as a yellow solid which was used into next step withoutfurther purification. MS (ESI) m/z 551.3[M+H].

To a solution ofN-(7-(2-azaspiro[3.3]heptan-6-ylethynyl)-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)acrylamide(40.0 mg, 72.6 umol, 1.00 eq), paraformaldehyde (12.0 mg, 399 umol, 11.0uL, 5.51 eq) in trifluoroethanol (1.00 mL) was added sodium borohydride(6.00 mg, 158 umol, 2.18 eq), the mixture was stirred at 60° C. for 2 h.The reaction was concentrated to give a residue, the residue waspurified by pre-HPLC (column: Phenomenex luna C18 150×25 10 u; mobilephase: [water (0.1% TFA)-ACN]; B %: 1%-31%, 12 min) to affordN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-((2-methyl-2-azaspiro[3.3]heptan-6-yl)ethynyl)quinazolin-6-yl)acrylamide124 (10.6 mg, 17.7 umol, 25% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.22-10.85 (m, 1H), 10.10 (s, 2H), 8.89 (s, 1H), 8.81 (s,1H), 8.64-8.59 (m, 1H), 7.95-7.89 (m, 2H), 7.86 (s, 1H), 7.67-7.59 (m,2H), 7.44-7.38 (m, 1H), 7.34 (d, 0.1=9.0 Hz, 1H), 6.66 (br dd, J=10.2,17.0 Hz, 1H), 6.38 (br d, J=17.2 Hz, 1H), 5.96-5.81 (m, 1H), 5.37-5.33(m, 2H), 4.27 (br d, J=5.4 Hz, 2H), 4.01 (td, J=5.8, 12.0 Hz, 4H),3.39-3.29 (m, 1H), 2.79 (br d, J=4.6 Hz, 3H), 2.72-2.62 (m, 2H). MS(ESI) m/z 565.5[M+H]

Synthesis of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of methoxymethyl(triphenyl)phosphonium:chloride (2.21 g,6.44 mmol, 1.36 eq) in tetrahydrofuran (10.0 mL) was added lithiumbis(trimethylsilyl)amide (1.00 M, 6.44 mL, 1.36 eq) dropwise at −78° C.The mixture was stirred at −78° C. for 0.5 h, then tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 4.73 mmol, 1.00 eq)in tetrahydrofuran (10.0 mL) was added dropwise at −78° C. The mixturewas rised to 25° C. slowly and stirred for 12 h. The mixture was dilutedwith water (30.0 mL) and extracted with ethyl acetate (3×20.0 mL). Thecombined organic layers were washed with water, dried over anhydroussodium sulfate, filtered and the filtrate was concentrated to afford aresidue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=20/1-10/1) to afford tert-butyl6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (760 mg, 3.18mmol, 67% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=5.64 (q,J=2.4 Hz, 1H), 3.76 (s, 4H), 3.40 (s, 3H), 2.70 (d, 0.1=2.4 Hz, 2H),2.63 (d, J=2.0 Hz, 2H), 1.28 (s, 9H).

To a solution of tert-butyl6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (2.50 g, 10.5mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added 1 M hydrochloricacid (30.0 mL) at 25° C. The mixture was stirred at 100° C. for 2 h. Themixture was basified with 4 M sodium hydroxide to PH=10-11, and addedanother sodium hydroxide (4.00 M, 5.75 mL, 2.2 eq) anddi-tert-butyldicarbonate (3.50 g, 16.04 mmol, 1.54 eq) at 25° C. Themixture was stirred at 25° C. for another 1 h. The mixture was extractedwith ethyl acetate (3×20.0 mL). The combined organic layers were washedwith water (20.0 mL), dried over anhydrous sodium sulfate, filtered andthe filtrate was concentrated to afford a residue. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=10/1-3/1) to afford tert-butyl6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (2.30 g, 10.2 mmol, 97%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=9.65 (d, J=1.6 Hz,1H), 3.87 (s, 2H), 3.76 (s, 2H), 2.38-2.26 (m, 4H), 1.36 (s, 9H).

To a solution of tert-butyl6-formyl-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl6-formyl-2-azaspiro[3.3]heptanes-2-carboxylate (2.70 g, 12.0 mmol, 1.00eq) and potassium carbonate (3.32 g, 24.0 mmol, 2.01 eq) in methanol(20.0 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (2.76 g,14.4 mmol, 1.20 eq) dropwise at 25° C. The mixture was stirred at 25° C.for 2 h. The reaction mixture was concentrated under reduced pressure togive a residue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=10/1) to afford tert-butyl6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (2.00 g, 9.04 mmol, 75%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=3.83 (d, J=4.4 Hz,4H), 2.80 (dq, J=2.4, 8.0 Hz, 1H), 2.46-2.38 (m, 2H), 2.26-2.17 (m, 2H),2.08 (d, J=2.4 Hz, 1H), 1.36 (s, 9H).

125: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 3-chloro-4-(pyridin-2-ylmethoxy)aniline; in step A.3 the OHnucleophile is 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide; variant ii)was used in step A.4; and variant i) was used in step A.5; and 44%overall yield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 1H), 9.58(s, 1H), 8.84 (s, 1H), 8.61-8.60 (m, 1H), 8.61 (d, J=4.3 Hz, 1H), 8.50(s, 1H), 8.22 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.89 (dt, J=1.7, 7.7 Hz,1H), 7.70 (dd, J=2.6, 8.9 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.38 (dd,J=5.1, 6.8 Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.68 (dd,J=10.4, 17.0 Hz, 1H), 6.32 (dd, J=1.8, 17.0 Hz, 1H), 5.90-5.79 (m, 1H),5.29 (s, 2H), 4.34 (t, J=5.4 Hz, 2H), 3.08 (s, 8H), 3.07-3.03 (m, 2H).MS (ESI) m/z 609.2 [M+H]⁺126: To a solution of4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6-nitroquinazolin-7-yltrifluoromethanesulfonate (800 mg, 1.44 mmol, 1.00 eq) (obtained bytriflation of the corresponding alcohol) and 4-ethynylquinuclidine (253mg, 1.87 mmol, 1.30 eq) in dimethyl formamide (10.0 mL) was addedcopper(I) iodide (54.8 mg, 288 umol, 0.20 eq),tetrakis(triphenylphosphine)palladium (166 mg, 144 umol, 0.100 eq) andtriethylamine (1.46 g, 14.4 mmol, 2.00 mL, 10.0 eq) at 25° C. undernitrogen atmosphere. Then the mixture was stirred at 25° C. for 6 h. Themixture was poured into ammonium hydroxide aqueous solution (100 mL) andextracted with ethyl acetate (3×100 mL). All organic phases werecombined, washed with brine (100 mL), dried over anhydrous sodiumsulfate and concentrated under vacuum to give a residue. The residue waspurified by column chromatography on silica gel (ethylacetate/methanol=1/0 to 1/1) to giveN-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(quinuclidin-4-ylethynyl)quinazolin-4-amine(300 mg, 310 umol, 21% yield, 55% purity) as a yellow solid. MS (ESI)m/z 541.3 [M+H]⁺

To a solution of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitro-7-(quinuclidin-4-ylethynyl) quinazolin 4-amine (300 mg,555 umol, 1.00 eq) in methanol (4.00 mL) was added a solution ofsaturated ammonium chloride (89.0 mg, 1.66 mmol, 3.00 eq) in water (1.00mL) and iron powder (155 mg, 2.77 mmol, 5.00 eq). The mixture wasstirred at 80° C. for 20 h. The mixture was diluted with methanol (50.0mL) and filtered to give a filtrate which was concentrated to give aresidue. The residue was washed with a solution of dimethylsulfoxide(3.00 mL) and methanol (1.00 mL). Then the mixture was filtered to givea filtrate which was purified by prep-HPLC (column: Phenomenex SynergiMax-RP 150*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:4%-34%, 10 min) and lyophilized to give 20 mg of product. The filtercake was dried under vacuum to give 230 mg of product. Total 250 mg ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(quinuclidin-4-ylethynyl)quinazoline-4,6-diamine (250 mg, 489 umol, 88% yield) was obtained as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.53 (br s, 1H), 8.59 (d,J=4.6 Hz, 1H), 8.32 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.88 (br d, J=1.7Hz, 1H), 7.70 (br d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.51 (s,1H), 7.37 (dd, J=5.1, 6.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 5.59 (br s,2H), 5.28 (s, 2H), 3.28 (m, 6H), 2.22-2.09 (m, 6H). MS (ESI) m/z 511.4[M+H]⁺

To a solution ofN⁴-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-(quinuclidin-4-ylethynyl)quinazoline-4,6-diamine(190 mg, 372 umol, 1.00 eq) in dimethyl formamide (2.00 mL) was addedtriethylamine (113 mg, 1.12 mmol, 3.00 eq), followed by a solution ofprop-2-enoyl prop-2-enoate (46.9 mg, 372 umol, 1.00 eq) in dimethylformamide (0.500 mL) dropwise at 0° C. The mixture was stirred at 0° C.for 10 min. The mixture was diluted with dimethyl formamide (2.00 mL) togive a solution. The solution was purified by prep-HPLC (column: XtimateC18 150*25 mm*5 um; mobile phase: [water (0.05% ammonia hydroxidev/v)−ACN]; B %: 56%-86%, 10 min) and lyophilized to give a crudeproduct. Then the crude product was purified again by prep-HPLC (column:Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−ACN]; B %: 56%-86%, 10 min). But no desired mass wasdetected and the sample on preparative column was rinsed by 0.1%trifluoroacetic acid in acetonitrile to give desired fraction. Thedesired fraction was lyophilized to give a product of the secondpurification, which was purified again by prep-HPLC (column: Phenomenexluna C18 150*25 10 u; mobile phase: [water (0.1% TFA)-ACN]; B %: 5%-35%,10 min) and lyophilized to giveN-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-(quinuclidin-4-ylethynyl)quinazolin-6-yl)acrylamide126 (5.68 mg, 8.36 umol, 2.25% yield, 99% purity, trifluoroacetic acidsalt) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=11.25-10.69 (m, 1H), 10.19-10.04 (m, 1H),9.91-9.57 (m, 1H), 8.90-8.70 (m, 2H), 8.65-8.58 (m, 1H), 7.95-7.90 (m,2H), 7.87-7.82 (m, 1H), 7.67-7.56 (m, 2H), 7.45-7.37 (m, 1H), 7.36-7.29(m, 1H), 6.66-6.52 (m, 1H), 6.42-6.31 (m, 1H), 5.94-5.83 (m, 1H),5.41-5.26 (s, 2H), 3.36-3.25 (m, 6H), 2.22-1.98 (m, 6H). MS (ESI) m/z565.3 [M+H]⁺

Synthesis of 4-ethynylquinuclidine

To a solution of quinuclidine-4-carbonitrile (900 mg, 6.61 mmol, 1.00eq) in toluene (10.0 mL) was added Diisobutylaluminium Hydride (1 M intoluene, 13.2 mL, 2.00 eq) at −78° C. Then the mixture was stirred at−78° C. for 1 h. The reaction mixture was quenched by addition sodiumsulfate decahydrate (15.0 g), and then filtered and the filtrate wasconcentrated under reduced pressure to give quinuclidine-4-carbaldehyde(1 g, crude) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.34 (s, 1H),2.77-2.75 (m, 6H), 1.48 (br d, J=2.4 Hz, 6H).

To a solution of quinuclidine-4-carbaldehyde (540 mg, 3.88 mmol, 1.00eq) and potassium carbonate (1.07 g, 7.76 mmol, 2.00 eq) in methanol(10.0 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (894 mg,4.66 mmol, 1.20 eq) at 0° C. Then the mixture was stirred at 25° C. for2 h. The reaction mixture was concentrated under reduced pressure togive a residue. The residue was purified by column chromatography(Silica, dichloromethane/methanol=10/1) to afford 4-ethynylquinuclidine(600 mg, crude) as colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ=2.98 (s, 1H), 2.87-2.81 (m, 6H), 1.69-1.64(m, 6H).

127: Synthesized according to general procedure A, wherein in stepA.2H₂N—X is 4-(4-chloro-3-fluoro-phenoxy)aniline; in step A.3 the OHnucleophile is 2-morpholinoethanol; variant ii) was used in step A.4;and variant i) was used in step A.5; and 14% overall yield from III. ¹HNMR (400 MHz, CDCl₃) δ=9.16 (s, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 7.84(s, 1H), 7.81-7.71 (m, 2H), 7.34 (t, J=8.6 Hz, 1H), 7.13-7.04 (m, 2H),6.88-6.73 (m, 2H), 6.55-6.42 (m, 2H), 5.87 (dd, J=2.0, 9.2 Hz, 1H), 4.36(t, J=5.4 Hz, 2H), 3.84-3.73 (m, 4H), 2.94 (t, J=5.4 Hz, 2H), 2.63 (brd, J=4.4 Hz, 3H), 2.61 (br s, 2H). MS (ESI) m/z 564.0 [M+H]

Synthesis of 4-(4-chloro-3-fluoro-phenoxy)aniline

To a solution of 1-fluoro-4-nitrobenzene (1.00 g, 7.09 mmol, 751 uL,1.00 eq) in dimethyl formamide (10.0 mL) was added4-chloro-3-fluoro-phenol (1.25 g, 8.50 mmol, 1.20 eq) and cesiumcarbonate (4.62 g, 14.1 mmol, 2.00 eq) at 25° C., the mixture wasstirred at 80° C. for 12 h. The reaction mixture was poured into water(60.0 mL) and the aqueous phase was extracted with ethyl acetate (3-40.0mL). The combined organic phase was washed with brine (30.0 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuum togive a residue. The residue was purified by silica gel chromatography(Petroleum ether/Ethyl acetate=10/1) to afford1-chloro-2-fluoro-4-(4-nitrophenoxy)benzene (1.80 g, 6.73 mmol, 95%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.31-8.23 (m, 2H),7.71 (t, J=8.8 Hz, 1H), 7.43 (dd, J=2.8, 10.2 Hz, 1H), 7.28-7.22 (m,2H), 7.12-7.06 (m, 1H).

A mixture of 1-chloro-2-fluoro-4-(4-nitrophenoxy)benzene (1.80 g, 6.73mmol, 1.00 eq), iron powder (1.13 g, 20.2 mmol, 3.00 eq), ammoniumchloride (1.80 g, 33.6 mmol, 5.00 eq) in methanol (20.0 mL) and water(10.0 mL) was stirred at 80° C. for 1 h. The reaction mixture was pouredinto methanol (50.0 mL) and stirred for 10 min, filter and the filtratewas concentrate to give a residue. The residue was poured into water(50.0 mL) and the aqueous phase was extracted with ethyl acetate (3×50.0mL). The combined organic phase was washed with brine (30.0 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuum togive 4-(4-chloro-3-fluoro-phenoxy)aniline (1.20 g, 5.05 mmol, 75% yield)as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ=7.54-7.45 (m, 1H), 6.89(dd, J=2.8, 11.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.72-6.67 (m, 1H),6.66-6.58 (m, 2H), 5.07 (s, 2H).

128: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline; in step A.3the OH nucleophile is 2-morpholinoethanol; variant ii) was used in stepA.4; and variant i) was used in step A.5; and 14% overall yield from I.¹H NMR (400 MHz, CDCl₃) δ=9.10 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.88(d, J=2.6 Hz, 1H), 7.69 (s, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.54-7.44 (m,2H), 7.10 (d, J=7.6 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.54-6.38 (m, 2H),5.86 (dd, J=1.7, 9.6 Hz, 1H), 5.26 (s, 2H), 4.35 (t, J=5.5 Hz, 2H),3.79-3.74 (m, 4H), 2.92 (t, J=5.4 Hz, 2K), 2.61 (br d, J=4.6 Hz, 4H),2.59 (s, 3H). MS (ESI) m/z 575.5 [M+H]⁺

Synthesis of 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline

To a solution 2-chloro-1-fluoro-4-nitrobenzene (1.00 g, 5.70 mmol, 1.00eq) and (6-methyl-2-pyridyl) methanol (842 mg, 6.84 mmol, 1.20 eq) indimethyl formamide (10.0 mL) was added potassium carbonate (1.57 g, 11.4mmol, 2.00 eq), then the mixture was stirred at 25° C. for 3 h undernitrogen. The reaction mixture was added water (50.0 mL) and extractedwith ethyl acetate (3×50.0 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated under reduced pressure togive 2-((2-chloro-4-nitrophenoxy)methyl)-6-methylpyridine (1.86 g,crude) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.34 (d, J=2.8 Hz,1H), 8.23 (dd, J=2.8, 9.2 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.46 (d,J=9.2 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 5.40 (s,2H), 2.49 (s, 3H).

To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-6-methylpyridine(1.86 g, 6.67 mmol, 1.00 eq) in dichloromethane (10.0 mL) and methanol(20.0 mL) was added nickel(ii) chloride hexahydrate (1.58 g, 6.67 mmol,1.00 eq). Then sodium borohydride (504 mg, 13.3 mmol, 2.00 eq) was addedto the reaction mixture at 25° C., the reaction mixture was stirred at25° C. for 1 h. The reaction mixture was filtered and the filter cakewas washed with dichloromethane (40.0 mL). The combined organic layerswere concentrated under reduced pressure to give a black solid, theblack solid was added water (40.0 mL) and extracted with ethyl acetate(3×40.0 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure to give3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline (1.27 g, 5.11 mmol,76.6% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.71 (t,J=7.7 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.90 (d,J=8.7 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 6.50-6.44 (m, 1H), 5.02 (s, 2H),4.93 (s, 2H), 2.47 (s, 3H).

129: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline; in step A.3the OH nucleophile is 3-morpholinopropan-1-ol; variant ii) was used instep A.4; and variant i) was used in step A.5; and 42% overall yieldfrom III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (br s, 1H), 9.59 (br s, 1H),8.84 (s, 1H), 8.49 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.77 (t, J=7.6 Hz,1H), 7.70 (dd, J=2.3, 8.9 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.27 (s, 1H),7.23 (dd, J=3.9, 8.3 Hz, 2H), 6.71 (br dd, J=10.0, 17.1 Hz, 1H), 6.32(dd, J=1.5, 17.0 Hz, 1H), 5.82 (br d, J=11.2 Hz, 1H), 5.24 (s, 2H), 4.27(br t, J=6.1 Hz, 2H), 3.59 (br t, J=4.3 Hz, 4H), 2.50-2.45 (m, 5H), 2.39(br s, 4H), 2.00 (quin, J=6.5 Hz, 2H). MS (ESI) m/z 589.5 [M+H]⁺130: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((3-fluorobenzyl)oxy)aniline; in step A.3 the OHnucleophile is 2-(4-methylpiperazin-1-yl)ethanol; variant ii) was usedin step A.4; and variant i) was used in step A.5; and 18% overall yieldfrom II. ¹H NMR (400 MHz, CDCl₃) δ=9.11 (s, 1H), 8.73 (s, 1H), 8.64 (s,1H), 7.85 (d, J=2.4 Hz, 1H), 7.64 (s, 1H), 7.51 (dd, J=2.4, 8.8 Hz, 1H),7.38 (dt, J=6.4, 7.8 Hz, 1H), 7.28-7.20 (m, 3H), 7.04 (dt, 1=1.6, 8.4Hz, 1H), 6.95 (d, 1=8.8 Hz, 1H), 6.55-6.37 (m, 2H), 5.85 (dd, J=1.8, 9.4Hz, 1H), 5.15 (s, 2H), 4.34 (t, J=5.4 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H),2.73-2.61 (m, 4H), 2.52 (br s, 4H), 2.32 (s, 3H). MS (ESI) m/z 591.4[M+H]⁺131: Synthesized according to general procedure C starting fromintermediate XIV obtained in analogy to the respective intermediate in28, wherein in step C₁₋₃ H₂NX is5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline C₁₋₄ HNR′R″ is3-methoxyazetidine hydrochloride; variant ii) was used in step C.5; andvariant ii) was used in step C₁₋₆; and 18% overall yield from XIV. ¹HNMR (400 MHz, CDCl₃) δ=9.16 (s, 1H), 8.70 (s, 1H), 8.44 (d, 1=8.3 Hz,1H), 8.30 (s, 1H), 7.44-7.37 (m, 1H), 7.34 (s, 1H), 7.30 (s, 1H),7.28-7.21 (m, 2H), 7.08-7.08 (m, 1H), 7.06 (dt, J=2.0, 8.4 Hz, 1H), 6.86(d, J=11.8 Hz, 1H), 6.57-6.46 (m, 1H), 6.45-6.28 (m, 1H), 5.89 (dd,J=1.2, 10.0 Hz, 1H), 5.16 (s, 2H), 4.31 (t, J=6.4 Hz, 2H), 4.08 (quin,J=5.8 Hz, 1H), 3.72-3.61 (m, 2H), 3.30 (s, 3H), 3.01-2.88 (m, 2H), 2.71(t, J=6.8 Hz, 2H), 2.01 (t, J=6.6 Hz, 2H). MS (ESI) m/z 610.5 [M+H]⁺132: Synthesized according to general procedure C starting fromintermediate XIV obtained in analogy to the respective intermediate in28, wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″ is8-oxa-3-azabicyclo[3.2.1]octane; variant ii) was used in step C.5; andvariant ii) was used in step C₁₋₆; and 4% overall yield from XIV. ¹H NMR(400 MHz, DMSO-d₆) δ=9.67 (s, 1H), 9.54 (s, 1H), 8.84 (s, 1H), 8.49 (s,1H), 8.27 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.70(dd, J=2.6, 9.0 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.31 (s, 1H), 7.23 (dd,J=4.2, 8.3 Hz, 2H), 6.69 (dd, J=10.2, 17.1 Hz, 1H), 6.31 (dd, J=1.8,17.0 Hz, 1H), 5.85-5.78 (m, 1H), 5.23 (s, 2H), 4.31 (t, J=5.7 Hz, 2H),4.19-4.15 (m, 2H), 2.78 (s, 2H), 2.64 (s, 2H), 2.52 (br s, 3H), 2.30 (brd, J=1.8 Hz, 2H), 1.82-1.76 (m, 2H), 1.67-1.61 (m, 2H). MS (ESI) m/z601.3 [M+H]⁺133: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline; in step A.3the OH nucleophile is R)-1-methylpyrrolidin-3-ol; variant ii) was usedin step A.4; and variant i) was used in step A.5; and 1% overall yieldfrom II. ¹H NMR (400 MHz, DMSO-d₆) δ=9.65 (s, 1H), 9.61 (s, 1H), 8.91(s, 1H), 8.37 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.49 (dt, J=6.1, 8.0 Hz,1H), 7.37-7.33 (m, 2H), 7.31 (s, 1H), 7.21 (dt, J=2.3, 8.7 Hz, 1H), 7.16(s, 1H), 6.76 (dd, J=10.3, 17.0 Hz, 1H), 6.32 (dd, J=1.8, 16.9 Hz, 1H),5.89-5.76 (m, 1H), 5.29 (s, 2H), 5.17-5.07 (m, 1H), 2.91-2.83 (m, 1H),2.82-2.74 (m, 2H), 2.43-2.34 (m, 2H), 2.29 (s, 3H), 2.06-1.96 (m, 1H).MS (ESI) m/z 566.4 [M+H]⁺134: Synthesized according to general procedure C starting fromintermediate XIV obtained in analogy to the respective intermediate in28, wherein in step C₁₋₃ H₂NX is5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline C₁₋₄ HNR′R″ is3-methoxyazetidine; variant ii) was used in step C.5; and variant ii)was used in step C₁₋₆; and 14% overall yield from XIV. ¹H NMR (400 MHz,DMSO-d₆) δ=9.64 (br s, 1H), 9.59 (s, 1H), 8.80 (s, 1H), 8.37 (s, 1H),7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=6.1 Hz, 1H), 7.36-7.32 (m, 2H), 7.31(s, 1H), 7.25 (s, 1H), 7.23-7.17 (m, 1H), 6.68 (dd, J=10.2, 17.0 Hz,1H), 6.31 (dd, J=1.8, 17.0 Hz, 1H), 5.88-5.75 (m, 1H), 5.29 (s, 2H),4.20 (t, J=5.2 Hz, 2H), 3.94 (quin, J=5.8 Hz, 1H), 3.61-3.55 (m, 2H),3.13 (s, 3H), 2.96 (dd, J=5.8, 8.2 Hz, 2H), 2.88 (t, J=5.3 Hz, 2H). MS(ESI) m/z 596.2 [M+H]⁺135: Synthesized according to general procedure C starting fromintermediate XIV obtained in analogy to the respective intermediate in28, wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″ is3-methoxyazetidine; variant ii) was used in step C.5; and variant ii)was used in step C₁₋₆; and 3% overall yield from XIV. ¹H NMR (400 MHz,DMSO-d₆) δ=9.66 (br d, J=17.7 Hz, 2H), 8.81 (s, 1H), 8.49 (s, 1H), 8.26(s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.70 (dd,J=2.6, 9.0 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.24 (d, J=6.0Hz, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.67 (dd, J=10.2, 17.1 Hz, 1H), 6.31(dd, J=1.9, 17.1 Hz, 1H), 5.84-5.78 (m, 1H), 5.23 (s, 2H), 4.20 (t,J=5.2 Hz, 2H), 3.94 (quin, J=5.7 Hz, 1H), 3.60-3.57 (m, 2H), 3.13 (s,3H), 2.99-2.96 (m, 2H), 2.88 (t, J=5.2 Hz, 2H), 2.52 (br d, J=2.0 Hz,3H). MS (ESI) m/z 575.3 [M+H]⁺136: To a solution ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-(3-methoxyazetidin-1-yl)propoxy)quinazoline-4,6-diamine (120 mg, 216 umol, 1.00 eq) andbut-2-ynoic acid (127 mg, 1.51 mmol, 7.00 eq) in pyridine (3.00 mL) wasadded propylphosphonic anhydride (961 mg, 1.51 mmol, 899 uL, 50% purity,7.00 eq) dropwise at 0° C. After addition, the mixture was stirred for 1h at 0° C. The reaction mixture was filtered and the filtrate waspurified by prep-HPLC (column. Waters Xbridge 150*25 5 u; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 40%-70%, 10 min) and lyophilized togiveN-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(3-(3-methoxyazetidin-1-yl)propoxy)quinazolin-6-yl)but-2-ynamide(7.86 mg, 12.4 umol, 5% yield, 98% purity) as an off-white solid. ¹H NMR(400 MHz, CDCl₃) δ=8.96 (s, 1H), 8.69 (s, 1H), 8.40 (d, J=8.2 Hz, 2H),7.43-7.38 (m, 1H), 7.35 (br s, 1H), 7.28-7.21 (m, 3H), 7.13-7.01 (m,1H), 6.85 (d, J=11.8 Hz, 1H), 5.16 (s, 2H), 4.30 (t, J=6.2 Hz, 2H), 4.09(quin, J=5.8 Hz, 1H), 3.74-3.65 (m, 2H), 3.30 (s, 3H), 3.01-2.90 (m,2H), 2.72 (t, J=6.8 Hz, 2H), 2.10 (s, 3H), 2.01 (t, J=6.8 Hz, 2H). MS(ESI) m/z 622.4 [M+H]⁺

Synthesis ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-(3-methoxyazetidin-1-yl)propoxy)quinazoline-4,6-diamine

Synthesized according to general procedure C starting from intermediateXIV wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″ is3-methoxyazetidine: variant ii) was used in step C.5; and variant ii)was used in step C₁₋₆ to giveN4-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-(3-methoxyazetidin-1-yl)propoxy)quinazoline-4,6-diamine. MS (ESI) m/z 535.3 [M+H]⁺. IntermediateXIV was obtained by adding sodium (659 mg, 28.7 mmol, 679 uL, 3.00 eq)to propane-1,3-diol (20.0 mL) in portions at 25° C. After the reactionturned clear, 7-fluoro-6-nitroquinazolin-4-ol (2.00 g, 9.56 mmol, 1.00eq) was added to the mixture in portions and the reaction mixture wasstirred at 25° C. for 4 h. To the reaction mixture was added hydrogenchloride (1.00 M) till pH to 3-4. Then the mixture was filtered andwashed with water. The filter cake was dried to give7-(3-hydroxypropoxy)-6-nitroquinazolin-4-ol (1.50 g, crude) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ=12.57 (br s, 1H), 8.60 (s, 1H), 8.31 (s,1H), 7.51 (s, 1H), 4.68 (t, J=5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.66(q, J=6.0 Hz, 2H), 1.99 (quin, J=6.0 Hz, 2H).

137: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline; in step A.3the OH nucleophile is 2-(4-methylpiperazin-1-yl)ethanol: variant ii) wasused in step A.4; and variant i) was used in step A.5; and 18% overallyield from III. ¹H NMR (400 MHz, DMSO-d₆) δ=9.67 (br s, 1H), 9.58 (br s,1H), 8.84 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.75 (t, J=7.7Hz, 1H), 7.72-7.66 (m, 1H), 7.37 (br d, J=7.6 Hz, 1H), 7.30 (s, 1H),7.22 (dd, J=5.1, 8.1 Hz, 2H), 6.68 (br dd, J=10.2, 16.9 Hz, 1H), 6.31(dd, J=1.6, 17.0 Hz, 1H), 5.81 (br d, J=10.4 Hz, 1H), 5.23 (s, 2H), 4.32(br t, J=5.5 Hz, 2H), 3.33-3.31 (m, 3H), 2.79 (br s, 2H), 2.52-2.51 (m,4H), 2.30 (br s, 4H), 2.13 (s, 3H). MS (ESI) m/z 588.4 [M+H]⁺138: Synthesized according to general procedure C starting fromintermediate XIV wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″ is3-methoxyazetidine; variant ii) was used in step C.5; and variant i) wasused in step C.6. ¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (br s, 1H), 9.61-9.49(m, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.76 (t,J=7.8 Hz, 1H), 7.69 (br d, J=7.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H),7.30-7.13 (m, 3H), 6.71 (br dd, J=10.2, 16.8 Hz, 1H), 6.32 (dd, J=1.8,17.0 Hz, 1H), 5.88-5.75 (m, 1H), 5.24 (s, 2H), 4.22 (br t, J=6.2 Hz,2H), 3.95 (t, J=5.8 Hz, 1H), 3.57-3.45 (m, 2H), 3.15 (s, 3H), 2.77 (dd,J=5.8, 7.8 Hz, 2H), 2.60-2.57 (m, 2H), 2.53 (br s, 3H), 1.93-1.77 (m,2H). MS (ESI) m/z 589.5 [M+H]⁺

Intermediate XIV was obtained by adding sodium (659 mg, 28.7 mmol, 679uL, 3.00 eq) to propane-1,3-diol (20.0 mL) in portions at 25° C. Afterthe reaction turned clear, 7-fluoro-6-nitroquinazolin-4-ol (2.00 g, 9.56mmol, 1.00 eq) was added to the mixture in portions and the reactionmixture was stirred at 25° C. for 4 h. To the reaction mixture was addedhydrogen chloride (1.00 M) till pH to 3-4. Then the mixture was filteredand washed with water. The filter cake was dried to give7-(3-hydroxypropoxy)-6-nitroquinazolin-4-ol (1.50 g, crude) as a whitesolid.

139: Synthesized according to general procedure C starting fromintermediate XII wherein in step C₁₋₃ H₂NX is3-chloro-4-((3-fluorobenzyl)oxy)aniline C₁₋₄ HNR′R″ is8-oxa-3-azabicyclo[3.2.1]octane; variant ii) was used in step C.5; andvariant i) was used in step C₁₋₆; and 29% overall yield from XIII. ¹HNMR (400 MHz, CDCl₃) δ=9.11 (s, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 7.89(d, J=2.5 Hz, 1H), 7.51 (dd, J=2.6, 8.8 Hz, 1H), 7.41-7.34 (m, 2H),7.26-7.21 (m, 1H), 7.07-7.01 (m, 1H), 7.01-6.96 (m, 1H), 6.58-6.45 (m,1H), 6.41-6.28 (m, 1H), 5.89 (dd, J=1.0, 10.2 Hz, 1H), 5.17 (s, 2H),4.36-4.30 (m, 4H), 2.89 (t, J=5.6 Hz, 2H), 2.67 (br d, J=10.5 Hz, 2H),2.52 (dd, J=1.9, 11.0 Hz, 2H), 1.94-1.87 (m, 4H). MS (ESI) m/z 604.4[M+H]⁺140: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline; in step A.3the OH nucleophile is (R)-1-methylpyrrolidin-3-ol; variant ii) was usedin step A.4; and variant i) was used in step A.5; and 18% overall yieldfrom III. ¹H NMR (400 MHz, CDCl₃) δ=9.13 (s, 1H), 8.63 (s, 1H), 8.58 (s,1H), 7.87 (d, J=2.6 Hz, 1H), 7.68-7.61 (m, 1H), 7.52-7.48 (m, 2H), 7.46(d, J=7.9 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.99 (d, J=8.9Hz, 1H), 6.53-6.45 (m, 1H), 6.44-6.35 (m, 1H), 5.88-5.80 (m, 1H), 5.27(s, 2H), 5.05 (br t, J=6.4 Hz, 1H), 3.11 (d, J=11.0 Hz, 1H), 3.05 (dt,=3.9, 8.7 Hz, 1H), 2.69 (dd, J=5.4, 11.1 Hz, 1H), 2.59 (s, 3H),2.56-2.47 (m, 1H), 2.44 (s, 3H), 2.37 (q, J=8.2 Hz, 1H), 2.19-2.10 (m,1H). MS (ESI) m/z 545.4 [M+H]⁺141: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-((2-methylpyridin-4-yl)methoxy)aniline; in step A.3the NH nucleophile is morpholine; variant ii) was used in step A.4; andvariant i) was used in step A.5, and 24% overall yield from 11. ¹H NMR(400 MHz, CDCl₃) δ=9.15 (s, 1H), 8.65 (s, 1H), 8.61-8.52 (m, 1H),7.93-7.85 (m, 1H), 7.59-7.43 (m, 2H), 7.42-7.35 (m, 1H), 7.28-7.22 (m,2H), 7.18 (br s, 1H), 7.04 (dt, J=2.4, 8.4 Hz, 1H), 7.01-6.96 (m, 1H),6.56-6.47 (m, 1H), 6.45-6.35 (m, 1H), 5.90-5.81 (m, 1H), 5.17 (s, 2H),5.06 (br s, 1H), 3.16-3.00 (m, 2H), 2.76-2.66 (m, 1H), 2.60-2.49 (m,1H), 2.46 (s, 3H), 2.43-2.34 (m, 1H), 2.23-2.08 (m, 2H). MS (ESI) m/z545.5 [M+H]⁺142: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((3-fluorobenzyl)oxy)aniline C.4

HNR′R″ is 8-oxa-3-azabicyclo[3.2.1]octane; variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 15% overall yield fromXIV. ¹H NMR (400 MHz, CDCl₃) δ=9.12 (s, 1H), 8.65 (s, 1H), 8.53 (d,J=5.1 Hz, 1H), 8.48 (s, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.51 (dd, J=2.6,8.9 Hz, 1H), 7.41 (s, 1H), 7.29 (s, 2H), 7.22 (d, J=4.9 Hz, 1H), 6.95(d, J=8.9 Hz, 1H), 6.54-6.47 (m, 1H), 6.43-6.32 (m, 1H), 5.88 (dd,J=1.0, 10.2 Hz, 1H), 5.15 (s, 2H), 4.37 (t, J=5.6 Hz, 2H), 3.78-3.74 (m,4H), 2.92 (t, J=5.5 Hz, 2H), 2.62-2.59 (m, 7H). MS (ESI) m/z 575.4[M+H]⁺

Synthesis of 3-chloro-4-((2-methylpyridin-4-yl)methoxy)aniline

To a solution of 2-methylisonicotinic acid (1.00 g, 7.29 mmol, 1.00 eq)in tetrahydrofuran (10.0 mL) was added borane-dimethyl sulfide complex(10 M, 1.82 mL, 2.50 eq) dropwaise at 0° C. The mixture was stirred at20° C. for 12 h, quenched with methanol (40.0 mL) and hydrochloric acid(1 M, 60.0 mL). The resulting mixture was basified with saturated sodiumbicarbonate (75.0 mL) and extracted with ethyl acetate (3×25.0 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated to afford (2-methylpyridin-4-yl)methanol (600 mg, 4.87mmol, 67% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.58 (d,J=6.1 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J=6.0 Hz, 1H), 5.64 (br t, J=5.1Hz, 1H), 4.65-4.58 (m, 2H), 2.61 (s, 3H).

To a solution of (2-methylpyridin-4-yl)methanol (500 mg, 4.06 mmol, 1.00eq) and potassium carbonate (1.12 g, 8.12 mmol, 2.00 eq) in acetonitrile(5.00 mL) was added 2-chloro-1-fluoro-4-nitrobenzene (713 mg, 4.06 mmol,1.00 eq). The mixture was stirred at 80° C. for 12 h. The mixture wasfiltered and concentrated to afford a residue. The residue was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=5/1 to 1/1)to afford 4-((2-chloro-4-nitrophenoxy)methyl)-2-methylpyridine (830 mg,2.98 mmol, 73% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ=8.55(d, J=5.1 Hz, 1H), 8.36 (d, J=2.8 Hz, 1H), 8.16 (dd, J=2.8, 9.1 Hz, 1H),7.25 (s, 1H), 7.20 (d, J=5.1 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 5.25 (s,2H), 2.61 (s, 3H).

To a solution of 4-((2-chloro-4-nitrophenoxy)methyl)-2-methylpyridine(730 mg, 2.62 mmol, 1.00 eq) in methanol (3.00 mL) and water (3.00 mL)was added iron powder (1.17 g, 21.0 mmol, 8.00 eq) and ammonium chloride(1.40 g, 26.2 mmol, 10.0 eq). The mixture was stirred at 80° C. for 2 h.The mixture was cooled to 25° C. and then concentrated in vacuum to givea residue.

The residue was diluted with water (20.0 mL) and extracted with ethylacetate (3-60.0 mL). The combined organic layers were washed with water(20.0 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give3-chloro-4-((2-methylpyridin-4-yl)methoxy)aniline (550 mg, 2.21 mmol,84% yield) as a brown oil. MS (ESI) m/z 249.8 [M+H]⁺

143: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((3-fluorobenzyl)oxy)aniline C.4

HNR′R″ 3-methoxyazetidine: variant ii) was used in step C.5; and varianti) was used in step C₁₋₆; and 11% overall yield from XV. ¹H NMR (400MHz, CDCl₃) δ=9.11 (s, 1H), 8.97 (br s, 1H), 8.64 (s, 1H), 7.88 (d,J=2.6 Hz, 1H), 7.57 (s, 1H), 7.50 (dd, J=2.6, 8.9 Hz, 1H), 7.41-7.33 (m,1H), 7.27-7.21 (m, 3H), 7.07-7.00 (m, 1H), 6.97 (d, J=8.8 Hz, 1H),6.56-6.42 (m, 2H), 5.89-5.80 (m, 1H), 5.16 (s, 2H), 4.22 (t, J=5.1 Hz,2H), 4.10 (t, J=5.7 Hz, 1H), 3.74 (br t, J=6.9 Hz, 2H), 3.29 (s, 3H),3.13 (dd, J=6.4, 7.3 Hz, 2H), 3.00 (t, J=5.0 Hz, 2H). MS (ESI) m/z 578.3[M+H]⁺

144: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″ 3-methoxyazetidine:variant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 16% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.12 (s, 1H),8.66 (s, 1H), 8.31 (s, 1H), 7.92-7.86 (m, 1H), 7.55-7.48 (m, 1H), 7.45(s, 1H), 7.42-7.35 (m, 1H), 7.28-7.22 (m, 3H), 7.05 (dt, J=2.8, 8.6 Hz,1H), 7.00 (d, J=8.8 Hz, 1H), 6.57 (s, 1H), 6.46-6.29 (m, 1H), 5.97-5.83(m, 1H), 5.18 (s, 2H), 4.30 (t, J=6.4 Hz, 2H), 4.08 (quin, J=5.8 Hz,1H), 3.71-3.62 (m, 2H), 3.30 (s, 3H), 3.00-2.91 (m, 2H), 2.71 (t, J=6.8Hz, 2H), 2.00 (quin, J=6.6 Hz, 2H). MS (ESI) m/z 592.4 [M+H]⁺145: Synthesized according to general procedure C starting fromintermediate XII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″1-methylpiperazine; variant ii) was used in step C.5; and variant i) wasused in step C₁₋₆; and 9% overall yield from XV. 1H NMR (400 MHz,DMSO-d6) δ=9.63 (s, 1H), 9.56 (s, 1H), 8.84 (s, 1H), 8.38 (s, 1H), 8.19(s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.49 (dt, J=6.0, 8.1 Hz, 1H), 7.36-7.33(m, 2H), 7.31 (d, J=2.0 Hz, 2H), 7.20 (dt, J=2.3, 8.4 Hz, 1H), 6.69 (dd,J=10.3, 17.0 Hz, 1H), 6.31 (dd, J=1.8, 17.0 Hz, 1H), 5.85-5.78 (m, 1H),5.29 (s, 2H), 4.33 (t, J=5.8 Hz, 2H), 2.82 (t, J=5.8 Hz, 2H), 2.52-2.51(m, 4H), 2.37-2.29 (m, 4H), 2.15 (s, 3H). MS (ESI) m/z 609.3 [M+H]⁺146: To a suspension ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline-4,6-diamine (180 mg, 324 umol, 1.00 eq), but-2-ynoicacid (273 mg, 3.24 mmol, 10.0 eq) (obtained as intermediate during thesynthesis of 145, after step C.5) in pyridine (0.900 mL) andtetrahydrofuran (2.70 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.44 g,2.27 mmol, 1.35 mL, 50% purity, 7.00 eq) at 0° C. The mixture wasstirred at 20° C. for 1 h. The mixture was diluted with saturated sodiumcarbonate (2.00 mL), water (3.00 mL) and extracted with ethyl acetate(3×10.0 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated to afford a residue. Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*50 10 u;mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B %:40%-70%, 10 min) and lyophilized to affordN-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-6-yl)but-2-ynamide(7.55 mg, 12.0 umol, 4% yield, 99% purity) as a yellow solid. 1H NMR(400 MHz, DMSO-d6) δ=10.09-9.41 (m, 2H), 8.56 (br d, J=9.3 Hz, 1H), 8.30(br d, J=4.5 Hz, 1H), 7.59 (br d, J=8.1 Hz, 1H), 7.52-7.44 (m, 1H),7.38-7.27 (m, 3H), 7.25-7.14 (m, 2H), 5.27 (s, 2H), 4.28 (br t, J=5.4Hz, 2H), 2.76 (br t, J=5.7 Hz, 2H), 2.52-2.52 (m, 4H), 2.38-2.30 (m,4H), 2.16 (s, 3H), 2.06 (br s, 3H). MS (ESI) m/z 621.3 [M+H]⁺147: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″8-oxa-3-azabicyclo[3.2.1]octane; variant ii) was used in step C.5; andvariant i) was used in step C₁₋₆; and 6% overall yield from XIV. ¹H NMR(400 MHz, CDCl₃) δ=9.15 (s, 1H), 8.68 (s, 1H), 8.41 (d, J=8.2 Hz, 1H),8.29 (br s, 1H), 7.43-7.33 (m, 2H), 7.29 (s, 1H), 7.25 (br d, J=7.9 Hz,2H), 7.05 (dt, J=2.4, 8.3 Hz, 1H), 6.85 (d, J=11.9 Hz, 1H), 6.55-6.46(m, 1H), 6.37 (d, J=10.1 Hz, 1H), 5.89 (dd, J=1.0, 10.1 Hz, 1H), 5.15(s, 2H), 4.36-4.30 (m, 4H), 2.90 (t, J=5.6 Hz, 2H), 2.68 (br d, J=10.6Hz, 2H), 2.52 (dd, J=1.7, 10.8 Hz, 2H), 1.94-1.88 (m, 4H). MS (ESI) m/z622.2 [M+H]⁺148: To a suspension of but-2-ynoic acid (178 mg, 2.11 mmol, 10.0 eq)and7-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-N⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)quinazoline-4,6-diamine(120 mg, 211 umol, 1.00 eq) (obtained as intermediate during thesynthesis of 147, after step C.5) in pyridine (0.600 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (941 mg,1.48 mmol, 880 uL, 50% purity, 7.00 eq) at 0° C. The mixture was stirredat 20° C. for 1 h. The mixture was diluted with saturated sodiumcarbonate (1.50 mL), water (10.0 mL) and extracted with ethyl acetate(3×25.0 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated to afford a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25 * 10 um; mobile phase: [water (0.225% formic acid)-acetonitrile];B %. 28%-58%, 9 min) and lyophilized to affordN-(7-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)-4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)but-2-ynamide(3.65 mg, 5.26 umol, 2% yield, 98% purity, formic acid) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ=8.95 (s, 1H), 8.67 (s, 1H), 8.40 (br s,1H), 8.34 (d, J=8.2 Hz, 1H), 7.46 (br s, 1H), 7.42-7.35 (m, 1H),7.27-7.19 (m, 3H), 7.12-6.99 (m, 1H), 6.84 (d, J=11.6 Hz, 1H), 5.15 (s,2H), 4.37-4.27 (m, 4H), 2.89 (t, 0.1=5.4 Hz, 2H), 2.67 (br d, J=10.4 Hz,2H), 2.52 (br d, J=10.9 Hz, 2H), 2.07 (s, 3H), 2.01-1.95 (m, 2H),1.94-1.87 (m, 2H). MS (ESI) m/z 634.2 [M+H]⁺.149: To a solution ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine(150 mg, 277 umol, 1.00 eq) and but-2-ynoic acid (93.1 mg, 1.11 mmol,4.00 eq) in dimethyl formamide (1.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg,1.11 mmol, 4.00 eq) and pyridine (131 mg, 1.66 mmol, 134 uL, 6.00 eq)and the mixture was stirred at 25° C. for 3 h. The mixture was dilutedwith dimethyl formamide (1.00 mL) to give a solution. The solution waspurified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 40%-70%, 10 min) and lyophilized togiveN-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)but-2-ynamide(34.07 mg, 55.5 umol, 20% yield, 99/a purity) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=9.91 (s, 1H), 9.64 (s, 1H), 8.59 (br s, 1H), 8.38(s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.49 (dt, J=6.2, 8.0 Hz, 1H), 7.34 (brd, J=7.6 Hz, 2H), 7.31 (s, 2H), 7.20 (dt, J=2.3, 8.6 Hz, 1H), 5.29 (s,2H), 4.32 (t, 0.1=5.7 Hz, 2H), 3.66-3.55 (m, 4H), 2.79 (t, 0.1=5.7 Hz,2H), 2.52 (m, 4H), 2.07 (br s, 3H). MS (ESI) m/z 608.4 [M+H]⁺

Synthesis ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine

Synthesized according to general procedure A, wherein in step A.2H₂N—X5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline; in step A.3 the NHnucleophile is 2-morpholinoethanol; variant i) was used in step A.4 togiveN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine.1H NMR (400 MHz, DMSO-d6) δ=9.09 (br s, 1H), 8.32-8.08 (m, 2H), 7.64 (d,J=8.0 Hz, 1H), 7.54-7.45 (m, 1H), 7.37-7.32 (m, 2H), 7.30 (s, 1H),7.25-7.17 (m, 1H), 7.11 (s, 1H) 5.50-5.12 (m, 3H), 4.28 (br t, J=5.6 Hz,2H), 3.74-3.51 (m, 5H), 2.83 (t, J=5.6 Hz, 2H) 2.56-2.53 (m, 4H). MS(ESI) m/z 542.3 [M+H]⁺

150: To a solutionN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine(200 mg, 359 umol, 1.00 eq) and but-2-ynoic acid (211 mg, 2.52 mmol,7.00 eq) in pyridine (3.00 mL) was added propylphosphonic anhydride(2.29 g, 3.60 mmol, 2.14 mL, 50% purity, 10.0 eq) dropwise at 0° C.After addition, the mixture was stirred at 0° C. for 1 h. The reactionmixture was filtered. The filtrate was purified by prep-HPLC (column:Waters X bridge 150*25 5 u; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 35%-65%, 10 min) and lyophilized to giveN-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)but-2-ynamide(10.68 mg, 16.4 umol, 5% yield, 95% purity) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ=8.97 (s, 1H), 8.69 (s, 1H), 8.43 (d, J=8.2 Hz,1H), 8.24 (s, 1H), 7.43-7.36 (m, 1H), 7.31 (s, 1H), 7.28-7.21 (m, 3H),7.11-6.99 (m, 1H), 6.86 (d, J=11.8 Hz, 1H), 5.16 (s, 2H), 4.34 (t, J=6.4Hz, 2H), 3.83-3.74 (m, 4H), 2.64-2.57 (m, 2H), 2.56-2.46 (m, 4H), 2.17(br t, J=6.8 Hz, 2H), 2.10 (s, 3H). MS (ESI) m/z 622.4 [M+H]

Synthesis ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine

Synthesized according to general procedure C starting from intermediateXIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″ morpholine;variant ii) was used in step C.5 to giveN-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine.MS (ESI) m/z 556.3 [M+H]⁺

151: To a solution of(R)—N-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-((1-methylpyrrolidin-3-yl)oxy)quinazoline-4,6-diamine (200 mg, 391 umol, 1.00 eq) (obtained asintermediate in the synthesis of 133 [V]) in dimethyl formamide (2.00mL) was added but-2-ynoic acid (49.3 mg, 586 umol, 1.50 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 781umol, 2.00 eq) and pyridine (92.7 mg, 1.17 mmol, 94.6 uL, 3.00 eq). Thenthe mixture was stirred at 25° C. for 1 h. The mixture was diluted withdimethyl formamide (1.00 mL) to give a solution. The solution waspurified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase:[water (10 mM NH₄HCO)-ACN]; B %: 42%-72%, 10 min) and lyophilized togive(R)—N-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)but-2-ynamide(51.17 mg, 84.9 umol, 22% yield, 96% purity) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=9.98 (br s, 1H), 9.63 (s, 1H), 8.63 (br s, 1H),8.37 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.53-7.44 (m, 1H), 7.38-7.28 (m,3H), 7.24-7.17 (m, 1H), 7.15 (s, 1H), 5.29 (s, 2H), 5.08 (br d, J=3.1Hz, 1H), 2.79 (br s, 2H), 2.77-2.70 (m, 1H), 2.42-2.35 (m, 2H), 2.29 (s,3H), 2.07 (br s, 3H), 1.98-1.87 (m, 1H). MS (ESI) m/z 578.3 [M+H]⁺152: To the suspension ofN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-(3-methoxyazetidin-1-yl)ethoxy)quinazoline-4,6-diamine (0.150 g, 277 umol, 1.00 eq)) (obtainedas intermediate in the synthesis of 134 [XVII]) in pyridine (15.0 mL)was added but-2-ynoic acid (0.116 g, 1.38 mmol, 5.00 eq) andpropylphosphonic anhydride (1.23 g, 1.94 mmol, 7.00 eq, 50% in ethylacetate) at 25° C. The mixture was stirred at 30° C. for 2 h. Theresidue was added saturated sodium carbonate (50.0 mL). The aqueousphase was extracted with ethyl acetate/methanol (8/1, 3×100 mL). Thecombined organic phase was washed with sodium carbonate (3×100 mL),concentrated under vacuum to afford a residue. The residue was purifiedby prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %: 42%-72%, 14 min) and lyophilized to affordN-(4-((5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(2-(3-methoxyazetidin-1-yl)ethoxy)quinazolin-6-yl)but-2-ynamide(68.38 mg, 111 umol, 40/o yield, 99/6 purity) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=10.01 (br s, 1H), 9.64 (s, 1H), 8.57 (br s, 1H),8.37 (s, 1H), 7.60 (br d, J=7.9 Hz, 1H), 7.49 (dt, J=6.0, 8.1 Hz, 1H),7.34 (br d, J=7.3 Hz, 2H), 7.31 (br s, 1H), 7.25-7.18 (m, 2H), 5.29 (s,2H), 4.16 (br t, J=5.1 Hz, 2H), 3.98 (quin, J=5.8 Hz, 1H), 3.62 (dd,J=6.1, 7.9 Hz, 2H), 3.16 (s, 3H), 2.98 (br t, J=6.9 Hz, 2H), 2.85 (br t,J=5.1 Hz, 2H), 2.06 (br s, 3H). MS (ESI) m/z 608.4 [M+H]⁺153: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl) methoxy)aniline C₁₋₄ HNR′R″morpholine; variant ii) was used in step C.5; and variant i) was used instep C.6; and 5% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.10(s, 1H), 8.65 (s, 1H), 8.20 (br s, 1H), 8.00-7.80 (m, 2H), 7.75 (s, 1H),7.65-7.46 (m, 2H), 6.98 (br d, J=8.8 Hz, 1H), 6.90 (br d, J=6.4 Hz, 1H),6.57-6.43 (m, 1H), 6.43-6.28 (m, 1H), 5.89 (br d, J=10.2 Hz, 1H), 5.22(s, 2H), 4.33 (br t, J=6.4 Hz, 2H), 3.76 (br t, J=4.2 Hz, 4H), 2.68-2.45(m, 6H), 2.14 (br t, J=6.8 Hz, 2H). MS (ESI) m/z 593.3 [M+H].154: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″morpholine; variant ii) was used in step C.5; and variant i) was used instep C₁₋₆; and 8% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.15(s, 1H), 8.74-8.60 (m, 2H), 8.37-8.21 (m, 1H), 7.94-7.80 (m, 2H),7.64-7.48 (m, 3H), 7.33 (s, 1H), 7.02-6.95 (m, 1H), 6.90 (dd, J=2.6, 8.1Hz, 1H), 6.56-6.41 (m, 2H), 5.89 (br dd, J=2.3, 9.0 Hz, 1H), 5.22 (d,J=3.8 Hz, 2H), 4.42-4.33 (m, 2H), 3.83-3.75 (m, 4H), 2.99 (t, J=5.4 Hz,2H), 2.68 (br s, 4H). MS (ESI) m/z 579.2 [M+H]⁺

Synthesis of 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline

To a solution of 2-fluoro-6-methylpyridine (8.00 g, 72.0 mmol, 7.41 mL,1.00 eq) in acetonitrile (200 mL) was added1-chloropyrrolidine-2,5-dione (24.0 g, 180 mmol, 2.50. eq), benzoicperoxyanhydride (2.09 g, 8.64 mmol, 0.120 eq) and acetic acid (0.400mL). The mixture was stirred at 85° C. for 12 h. The mixture wasconcentrated to afford a residue. The residue was diluted with water(50.0 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0-10/1) to afford2-(chloromethyl)-6-fluoropyridine (4.50 g, 30.9 mmol, 43% yield) as acolorless oil. MS (ESI) m/z 145.9 [M+H]⁺

To a solution of 2-(chloromethyl)-6-fluoropyridine (2.00 g, 13.7 mmol,0.750 eq) in acetonitrile (40.0 mL) was added potassium carbonate (2.53g, 18.3 mmol, 1.00 eq), followed by the addition of4-amino-2-chlorophenol (2.63 g, 18.3 mmol, 1.00 eq), potassium iodide(304 mg, 1.83 mmol, 0.100 eq) and potassium hydroxide (1.03 g, 18.3mmol, 1.00 eq). The mixture was stirred at 90° C. for 12 h. The mixturewas concentrated to afford a residue. The residue was diluted with water(100 mL) and extracted with ethyl acetate (3×200 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated to afford a residue. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/1) to afford3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (1.10 g, 4.35 mmol,24% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=7.83 (q, J=7.9Hz, 1H), 7.60-7.50 (m, 1H), 6.86 (dd, J=2.1, 8.2 Hz, 1H), 6.81-6.75 (m,2H), 6.52 (dd, J=2.8, 8.6 Hz, 1H), 5.10 (s, 2H), 3.54 (br s, 2H).

155: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″3-methoxyazetidine; variant ii) was used in step C.5; and variant i) wasused in step C₁₋₆; and 11% overall yield from XIV. ¹H NMR (400 MHz,CDCl₃) δ=9.11 (s, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.93-7.84 (m, 2H),7.58 (dd, J=1.6, 7.6 Hz, 1H), 7.52 (dd, J=2.6, 8.9 Hz, 1H), 7.42 (s,1H), 7.27-7.26 (m, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.90 (dd, J=2.1, 8.2 Hz,1H), 6.55-6.48 (m, 1H), 6.43-6.34 (m, 1H), 5.89 (dd, J=1.2, 10.1 Hz,1H), 5.23 (s, 2H), 4.29 (t, J=6.3 Hz, 2H), 4.06 (t, J=5.8 Hz, 1H), 3.66(dd, J=6.1, 8.3 Hz, 2H), 3.28 (s, 3H), 2.97-2.92 (m, 2H), 2.70 (t, J=6.8Hz, 2H), 1.99 (quin, J=6.7 Hz, 2H). MS (ESI) m/z 593.2 [M+H]⁺156: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″8-oxa-3-azabicyclo[3.2.1]octane; variant ii) was used in step C.5; andvariant i) was used in step C₁₋₆; and 11% overall yield from XIV. ¹H NMR(400 MHz, DMSO-d₆) δ=9.69 (s, 1H), 9.55 (s, 1H), 8.86 (s, 1H), 8.50 (s,1H), 8.28 (s, 1H), 8.09 (q, J=8.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.72(dd, J=2.4, 9.0 Hz, 1H), 7.54 (dd, J=2.4, 7.4 Hz, 1H), 7.32 (s, 1H),7.25 (d, J=9.0 Hz, 1H), 7.17 (dd, J=2.4, 8.0 Hz, 1H), 6.70 (dd, J=10.2,17.2 Hz, 1H), 6.32 (dd, J=2.0, 17.0 Hz, 1H), 5.87-5.77 (m, 1H), 5.26 (s,2H), 4.32 (t, J=5.6 Hz, 2H), 4.18 (dd, J=2.0, 4.2 Hz, 2H), 2.79 (t,J=5.6 Hz, 2H), 2.66 (d, J=10.8 Hz, 2H), 2.32 (dd, J=1.8, 11.1 Hz, 2H),1.85-1.77 (m, 2H), 1.69-1.60 (m, 2H). MS (ESI) m/z 605.5 [M+H]⁺157: Synthesized according to general procedure C starting fromintermediate XII I obtained in analogy to 28 wherein in step C₁₋₃ H₂NXis 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C.4 HNR′R″3-methoxyazetidine; variant ii) was used in step C.5; and variant i) wasused in step C₁₋₆; and 8% overall yield from XV. ¹H NMR (400 MHz,DMSO-d₆) δ=11.76-11.52 (m, 1H), 11.11 (br s, 1H), 10.44 (s, 1H), 9.19(s, 1H), 8.82 (s, 1H), 8.10 (q, J=8.2 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H),7.61 (dd, J=2.4, 8.8 Hz, 1H), 7.55 (dd, J=2.4, 7.2 Hz, 1H), 7.42 (s,1H), 7.34 (d, J=9.0 Hz, 1H), 7.26 (br dd, J=10.0, 17.0 Hz, 1H), 7.18(dd, J=2.4, 8.2 Hz, 1H), 6.36 (dd, J1=1.6, 17.2 Hz, 1H), 5.89-5.81 (m,1H), 5.31 (s, 2H), 4.57-4.44 (m, 3H), 4.40-4.31 (m, 1H), 4.29-4.21 (m,1H), 4.20-4.01 (m, 2H), 3.84-3.73 (m, 2H), 3.29-3.26 (m, 3H). MS (ESI)m/z 579.3 [M+H]⁺158: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is(3-chloro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″ 1-methylpiperazine;variant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 22% overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.75-9.66 (m,1H), 9.58 (s, 1H), 8.85 (s, 1H), 8.50 (s, 1H), 8.09 (q, J=8.4 Hz, 1H),8.01 (d, J=2.6 Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 7.54 (dd, J=2.2,7.6 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 7.17 (dd, 1=2.4, 8.2Hz, 1H), 6.69 (dd, J=10.2, 17.0 Hz, 1H), 6.32 (dd, J=1.8, 17.2 Hz, 1H),5.86-5.79 (m, 1H), 5.26 (s, 2H), 4.33 (t, J=5.6 Hz, 2H), 2.82 (t, J=5.8Hz, 2H), 2.57-2.51 (m, 4H), 2.37-2.23 (m, 4H), 2.14 (s, 3H). MS (ESI)m/z 592.5 [M+H]159: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is(3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane; variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 52% overall yield fromXV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.67 (s, 1H), 9.59 (s, 1H), 8.84 (s,1H), 8.49 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H),7.53-7.45 (m, 1H), 7.36-7.30 (m, 2H), 7.28-7.23 (m, 2H), 7.22-7.16 (m,1H), 6.72 (dd, J=10.2, 17.0 Hz, 1H), 6.32 (dd, J=2.0, 17.0 Hz, 1H),5.86-5.79 (m, 1H), 5.25 (s, 2H), 4.33 (s, 1H), 4.28 (t, J=6.4 Hz, 2H),3.85 (d, J=7.6 Hz, 1H), 3.50 (dd, J=1.8, 7.4 Hz, 1H), 3.47 (s, 1H),2.84-2.78 (m, 1H), 2.78-2.64 (m, 2H), 2.42 (d, J=9.6 Hz, 1H), 1.93(quin, J=6.8 Hz, 2H), 1.77-1.70 (m, 1H), 1.61-1.54 (m, 1H). MS (ESI) m/z604.2 [M+H]160: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((3-fluorobenzyl)oxy)aniline C.4 HNR′R″(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane; variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 41% overall yield fromXIV. ¹H NMR (400 MHz, CDCl₃) δ=9.00 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H),7.74 (d, J=2.8 Hz, 1H), 7.67 (s, 1H), 7.41 (dd, J=2.6, 8.8 Hz, 1H), 7.29(dt, J=5.8, 8.0 Hz, 1H), 7.18-7.12 (m, 3H), 6.99-6.92 (m, 1H), 6.84 (d,J=8.8 Hz, 1H), 6.45-6.37 (m, 1H), 6.33-6.23 (m, 1H), 5.83-5.76 (m, 1H),5.06 (s, 2H), 4.35 (s, 1H), 4.21 (t, J=6.4 Hz, 2H), 3.97 (d, J=7.6 Hz,1H), 3.57 (dd, J=1.6, 7.8 Hz, 1H), 3.41 (s, 1H), 2.89 (dd, J=1.6, 9.8Hz, 1H), 2.80-2.72 (m, 1H), 2.71-2.60 (m, 1H), 2.47 (d, J=10.0 Hz, 1H),2.04-1.94 (m, 2H), 1.80 (dd, J=1.8, 9.8 Hz, 1H), 1.73-1.64 (m, 1H). MS(ESI) m/z 604.5 [M+H]161: Synthesized according to general procedure C starting fromintermediate XII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane; variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 3% overall yield from XV.¹H NMR (400 MHz, DMSO-d₆) δ=9.68 (s, 1H), 9.60 (s, 1H), 8.85 (s, 1H),8.50 (s, 1H), 8.20 (s, 1H), 8.09 (q, J=8.2 Hz, 1H), 8.01 (d, J=2.6 Hz,1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 7.54 (dd, J=2.0, 7.4 Hz, 1H),7.30-7.23 (m, 2H), 7.17 (dd, J=2.4, 8.2 Hz, 1H), 6.72 (dd, J=10.2, 17.0Hz, 1H), 6.32 (dd, J=1.8, 17.2 Hz, 1H), 5.89-5.77 (m, 1H), 5.26 (s, 2H),4.34 (s, 1H), 4.28 (t, J=6.2 Hz, 2H), 3.85 (d, J=7.2 Hz, 1H), 3.51 (brd, J=1.6 Hz, 1H), 3.49 (br s, 1H), 2.82 (dd, J=1.6, 9.6 Hz, 1H),2.77-2.66 (m, 2H), 2.44 (d, J=9.8 Hz, 1H), 1.94 (quin, J=6.8 Hz, 2H),1.74 (dd, J=1.6, 9.4 Hz, 1H), 1.62-1.52 (m, 1H). MS (ESI) m/z 605.5[M+H]162: Synthesized according to general procedure C starting fromintermediate XII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline C₁₋₄ HNR′R″(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane; variant ii) was used in stepC.5; and variant i) was used in step C₁₋₆; and 55% overall yield fromXV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (br s, 1H), 9.62 (s, 1H), 8.85 (s,1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.09 (q, J=8.2 Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 7.71 (dd, J=2.4, 9.0 Hz, 1H), 7.54 (dd, J=2.4, 7.4 Hz, 1H),7.28-7.23 (m, 2H), 7.17 (dd, 1=2.4, 8.2 Hz, 1H), 6.73 (dd, J=10.2, 16.9Hz, 1H), 6.32 (dd, J=1.8, 17.0 Hz, 1H), 5.86-5.79 (m, 1H), 5.26 (s, 2H),4.36 (s, 1H), 4.28 (br t, J=6.2 Hz, 2H), 3.87 (d, J=7.8 Hz, 1H), 3.57(br s, 1H), 3.52 (br d, J=7.8 Hz, 1H), 2.88-2.78 (m, 2H), 2.77-2.69 (m,1H), 2.49-2.47 (m, 1H), 1.96 (quin, J=6.6 Hz, 2H), 1.78 (br d, J=9.4 Hz,1H), 1.61 (br d, J=9.0 Hz, 1H). MS (ESI) m/z 605.3 [M+H]163: Synthesized according to general procedure C starting fromintermediate XII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrimidin-4-ylmethoxy)aniline C.4 HNR′R″ morpholine; variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 22%overall yield from XIV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.22 (d, 1=1.2 Hz,1H), 9.10 (s, 1H), 8.82 (d, J=5.2 Hz, 1H), 8.64 (s, 1H), 8.32 (s, 1H),7.98 (br s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.59(dd, J=2.4, 8.8 Hz, 1H), 6.98 (d, 1=8.8 Hz, 1H), 6.55-6.39 (m, 2H), 5.89(dd, J=1.6, 9.8 Hz, 1H), 5.25 (s, 2H), 4.32 (t, J=6.4 Hz, 2H), 3.82-3.74(m, 4H), 2.63 (t, J=7.2 Hz, 2H), 2.56 (br d, J=4.0 Hz, 4H), 2.19-2.16(m, 2H). MS (ESI) m/z 576.2 [M+H]

Synthesis of 3-chloro-4-(pyrimidin-4-ylmethoxy)aniline

To a solution of 2-chloro-1-fluoro-4-nitro-benzene (1.59 g, 9.08 mmol,1.00 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate(2.51 g, 18.2 mmol, 2.00 eq) and pyrimidin-4-ylmethanol (1.00 g, 9.08mmol, 1.05 eq). The mixture was stirred at 60° C. for 24 h. The reactionmixture was added water (100 mL), filtered and the filter cake wasconcentrated under reduced pressure to give4-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.50 g, 5.65 mmol, 62%yield) as a yellow solid.

MS (ESI) m/z 265.9 [M+H]⁺

A mixture of 4-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.50 g, 5.65mmol, 1.00 eq), iron powder (1.58 g, 28.2 mmol, 5.00 eq) and ammoniumchloride (2.42 g, 45.2 mmol, 8.00 eq) in methanol (15.0 mL) and water(8.00 mL) was stirred at 80° C. for 2 h. The mixture was filtered andthe filtrate was concentrated to give a residue. The residue was pouredinto water (30.0 mL) and stirred for 10 min. The aqueous phase wasextracted with ethyl acetate (3×20.0 mL). The combined organic phase waswashed with brine (30.0 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuum to give3-chloro-4-(pyrimidin-4-ylmethoxy)aniline (1.10 g, 4.67 mmol, 83% yield)as a yellow solid.

164: To a solution ofN⁴-(3-chloro-4-(pyrimidin-4-ylmethoxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine(60.0 mg, 115 umol, 1.00 eq) (obtained as intermediate XVII during thesynthesis of 163) and but-2-ynoic acid (29.0 mg, 345 umol, 3.00 eq) inpyridine (0.500 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (220 mg,1.15 mmol, 10.0 eq) at 25° C. The mixture was stirred at 20° C. for 2 h.The mixture was poured into water (20.0 mL) and extracted with ethylacetate (3×20.0 mL). The combined organic phase was washed with brine(30.0 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give a residue. The residue was purified byprep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water(10 mM NH4HCO3)-ACN]; B %: 20%/6-50%, 10 min) to giveN-(4-((3-chloro-4-(pyrimidin-4-ylmethoxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)but-2-ynamide(35.58 mg, 60.5 umol, 52% yield) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ=9.98 (br s, 1H), 9.67 (s, 1H), 9.21 (d, J=1.4 Hz, 1H),8.89 (d, J=5.2 Hz, 1H), 8.59 (br s, 1H), 8.51 (s, 1H), 8.03 (d, J=2.0Hz, 1H), 7.74-7.67 (m, 2H), 7.28-7.23 (m, 2H), 5.34 (s, 2H), 4.23 (t,J=6.2 Hz, 2H), 3.60 (t, J=4.6 Hz, 4H), 2.49-2.46 (m, 2H), 2.40 (br s,4H), 2.07 (br s, 3H), 2.01-1.94 (m, 2H). MS (ESI) m/z 588.3 [M+H]165: To a solution ofN⁴-(3-chloro-4-(pyridazin-3-ylmethoxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine(200 mg, 383 umol, 1.00 eq) (obtained as intermediate &XVII for 167) andbut-2-ynoic acid (96.6 mg, 1.15 mmol, 3.00 eq) in pyridine (2.00 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (734mg, 3.83 mmol, 10.0 eq) at 25° C. The mixture was stirred at 25° C. for2 h. The mixture was poured into water (20.0 mL) and extracted withethyl acetate (3×20.0 mL). The combined organic phase was washed withbrine (30.0 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give a residue. The residue was purified byprep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water(10 mM NH4HCO3)-ACN]; B %: 19/6-49%, 10 min) to giveN-(4-((3-chloro-4-(pyridazin-3-ylmethoxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)but-2-ynamide (62.5mg, 106 mmol, 28% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=9.23-9.13 (m, 1H), 8.91 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 7.97-7.86(m, 2H), 7.82 (s, 1H), 7.63-7.49 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 5.54(s, 2H), 4.33 (t, J=6.4 Hz, 2H), 3.81-3.71 (m, 4H), 2.59 (t, J=7.2 Hz,2H), 2.52 (br s, 4H), 2.16 (br t, J=6.6 Hz, 2H), 2.09 (s, 3H). MS (ESI)m/z 588.1 [M+H]166: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrimidin-2-ylmethoxy)aniline C.4 HNR′R″ morpholine; variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 10%overall yield from XV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.66 (s, 1H), 9.60(s, 1H), 8.87 (d, J=4.9 Hz, 2H), 8.83 (s, 1H), 8.48 (s, 1H), 8.17 (s,1H), 7.95 (d, J=2.5 Hz, 1H), 7.63 (dd, J=2.5, 9.0 Hz, 1H), 7.50 (t,J=4.9 Hz, 1H), 7.27 (s, 1H), 7.11 (d, J=9.1 Hz, 1H), 6.71 (dd, J=10.2,16.9 Hz, 1H), 6.32 (dd, J=1.9, 17.0 Hz, 1H), 5.88-5.77 (m, 1H), 5.40 (s,2H), 4.26 (t, J=6.3 Hz, 2H), 3.59 (t, J=4.5 Hz, 4H), 2.49-2.46 (m, 2H),2.39 (br s, 4H), 1.99 (quin, J=6.7 Hz, 2H). MS (ESI) m/z 576.1 [M+H]⁺

Synthesis of 3-chloro-4-(pyrimidin-2-ylmethoxy)aniline

To a solution of 2-chloro-1-fluoro-4-nitrobenzene (1.00 g, 5.70 mmol,1.00 eq) and pyrimidin-2-ylmethanol (627 mg, 5.70 mmol, 1.00 eq) indimethyl formamide (8.00 mL) was added potassium carbonate (1.57 g, 11.4mmol, 2.00 eq) and the mixture was stirred at 60° C. for 16 h. Themixture was poured into water (25.0 mL) and some precipitate wasseparated out. Then the mixture was filtered and the filter cake wascollected. The filter cake was washed with petroleum ether and ethylacetate (5.00 mL, 5/1) and the mixture was filtered to give2-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.00 g, 3.69 mmol, 64%yield, 98% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.80 (d,J=4.9 Hz, 2H), 8.33 (d, J=2.7 Hz, 1H), 8.09 (dd, J=2.7, 9.2 Hz, 1H),7.31 (t, 1=4.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 5.51 (s, 2H).

To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.00 g,3.76 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution ofammonium chloride (604 mg, 11.3 mmol, 3.00 eq) in water (2.50 mL) andiron powder (1.05 g, 18.8 mmol, 5.00 eq). Then the mixture was stirredat 80° C. for 2 h. To the mixture was added methanol (10.0 mL) and themixture was filtered to give a filtrate, which was concentrated undervacuum to give a residue. To the residue was added ethyl acetate (15.0mL) and saturated sodium bicarbonate (5.00 mL). And the mixture wasextracted with ethyl acetate (2×15.0 mL). All organic phases werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to give 3-chloro-4-(pyrimidin-2-ylmethoxy)aniline (880 mg,3.47 mmol, 92% yield, 93% purity) as a brown solid was used into nextstep without further purification. ¹H NMR (400 MHz, CDCl₃) δ=8.79 (d,J=4.9 Hz, 2H), 7.25 (t, J=4.9 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.76 (d,J=2.8 Hz, 1H), 6.49 (dd, J=2.8, 8.7 Hz, 1H), 5.27 (s, 2H), 3.50 (br s,2H).

167: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyridazin-3-ylmethoxy)aniline C.4 HNR′R″ morpholine; variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 21%overall yield from XIV. 1H NMR (400 MHz, CDCl3) δ=9.19 (dd, J=1.6, 5.0Hz, 1H), 9.11 (s, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 7.99-7.88 (m, 2H),7.78 (s, 1H), 7.62-7.53 (m, 2H), 7.30 (s, 1H), 7.09 (d, J=8.8 Hz, 1H),6.55-6.47 (m, 1H), 6.42-6.32 (m, 1H), 5.90 (dd, J=1.0, 10.2 Hz, 1H),5.55 (s, 2H), 4.34 (t, J=6.4 Hz, 2H), 3.82-3.73 (m, 4H), 2.58 (t, J=7.2Hz, 2H), 2.52 (br d, J=4.4 Hz, 4H), 2.15 (quin, J=6.8 Hz, 2H). MS (ESI)m/z 576.2 [M+H].

Synthesis of 3-chloro-4-(pyridazin-3-ylmethoxy)aniline

To a solution of pyridazin-3-ylmethanol (1.00 g, 9.08 mmol, 1.00 eq) and2-chloro-1-fluoro-4-nitro-benzene (1.59 g, 9.08 mmol, 1.00 eq) indimethyl formamide (10.0 mL) was added potassium carbonate (2.51 g, 18.2mmol, 2.00 eq). The mixture was stirred at 60° C. for 12 h. The mixturewas concentrated to dryness to give a residue. The residue wastriturated with water (100 mL), filtered and the filter cake was washwith water (30.0 mL). The filter cake was dried to give3-((2-chloro-4-nitrophenoxy)methyl)pyridazine (2.30 g, 8.66 mmol, 95%yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ=9.25-9.23 (m, 1H),8.36 (d, J=2.8 Hz, 1H), 8.22-8.18 (m, 1H), 7.89-7.85 (m, 1H), 7.65-7.60(m, 1H), 7.21 (d, J=9.2 Hz, 1H), 5.64 (s, 2H). MS (ESI) m/z 266.0 [M+H]

A mixture of 3-((2-chloro-4-nitrophenoxy)methyl)pyridazine (2.30 g, 8.66mmol, 1.00 eq), iron powder (2.42 g, 43.3 mmol, 5.00 eq) and ammoniumchloride (2.32 g, 43.3 mmol, 5.00 eq) in methanol (20.0 mL) and water(5.00 mL) was stirred at 80° C. for 1 h. To the mixture was addedmethanol (100 ml) and filtered, the filtrate was concentrated to give aresidue. The residue was poured into water (30.0 mL) and stirred for 10min. The aqueous phase was extracted with ethyl acetate (3/20.0 mL). Thecombined organic phase was washed with brine (30.0 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to give3-chloro-4-(pyridazin-3-ylmethoxy)aniline (1.77 g, 7.51 mmol, 87% yield)as a brown solid.

168: To a solution ofN⁴-(3-chloro-4-(pyrimidin-2-ylmethoxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine(70.0 mg, 134 umol, 1.00 eq) (obtained as intermediate XVII during thesynthesis of 166) and but-2-ynoic acid (33.8 mg, 402 umol, 3.00 eq) inpyridine (1.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (257 mg,1.34 mmol, 10.0 eq) at 25° C. The mixture was stirred at 25° C. for 2 h.The mixture was poured into water (20.0 mL) and extracted with ethylacetate (3×20.0 mL). The combined organic phase was washed with brine(30.0 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to give a residue. The residue was purified by prep-HPLC(column: Xtimate C18 150*40 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)−ACN]; B %: 23%-53%, 10 min) to giveN-(4-((3-chloro-4-(pyrimidin-2-ylmethoxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)but-2-ynamide(62.5 mg, 106 mmol, 28% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ=8.91 (s, 1H), 8.83 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 8.26(s, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.54-7.45 (m, 2H), 7.30 (s, 1H), 7.03(d, J=8.8 Hz, 1H), 5.42 (s, 2H), 4.33 (t, J=6.6 Hz, 2H), 3.80-3.73 (m,4H), 2.59 (t, J=7.2 Hz, 2H), 2.53 (br d, J=4.4 Hz, 4H), 2.16 (quin,J=6.8 Hz, 2H), 2.09 (s, 3H). MS (ESI) m/z 588.2 [M+H].169: Synthesized according to general procedure A, wherein in stepA.2H₂N—X 3-chloro-4-(pyrazin-2-ylmethoxy) aniline; in step A.3 the OHnucleophile is 3-morpholinopropan-1-ol; variant i) was used in step A.4to giveN⁴-(5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)phenyl)-7-(2-morpholinoethoxy)quinazoline-4,6-diamine.¹H NMR (400 MHz, DMSO-d₆) δ=9.70 (s, 1H), 9.61 (s, 1H), 8.90-8.80 (m,2H), 8.74-8.64 (m, 2H), 8.50 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.73 (dd,J=2.6, 8.9 Hz, 1H), 7.32 (d, 1=9.0 Hz, 1H), 7.28 (s, 1H), 6.72 (dd,1=10.3, 17.0 Hz, 1H), 6.32 (dd, J=1.9, 17.1 Hz, 1H), 5.89-5.73 (m, 1H),5.38 (s, 2H), 4.27 (t, J=6.2 Hz, 2H), 3.58 (t, J=4.5 Hz, 4H), 2.48-2.46(m, 2H), 2.38 (br s, 4H), 2.00 (quin, J=6.6 Hz, 2H). MS (ESI) m/z 576.3[M+H]⁺

Synthesis of 3-chloro-4-(pyrazin-2-ylmethoxy) aniline

To a solution of 2-chloro-1-fluoro-4-nitro-benzene (3.00 g, 17.0 mmol,1.00 eq) and pyrazin-2-ylmethanol (2.00 g, 18.1 mmol, 1.06 eq) indimethyl formamide (20.0 mL) was added potassium carbonate (3.78 g, 27.3mmol, 1.60 eq) and the reaction mixture was stirred at 60° C. for 12 h.The reaction mixture was diluted with water (30.0 mL), filtered and thefilter cake was concentrated under reduced pressure to give2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (4.00 g, 15.0 mmol, 88%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-do) δ=8.88 (d, J=1.3 Hz,1H), 8.76-8.65 (m, 2H), 8.36 (d, J=2.1 Hz, 1H), 8.26 (dd, J=2.8, 9.2 Hz,1H), 7.54 (d, J=9.2 Hz, 1H), 5.56 (s, 2H).

To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (4.00 g,15.0 mmol, 1.00 eq) and iron powder (4.20 g, 75.2 mmol, 5.00 eq) inmethanol (60.0 mL) and water (10.0 mL) was added saturated ammoniumchloride (6.44 g, 120 mmol, 8.00 eq) and the mixture was stirred at 80°C. for 6 h. The reaction mixture was filtered and concentrated underreduced pressure to give a residue. The residue was diluted with water(50.0 mL) and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with brine (50.0 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give3-chloro-4-(pyrazin-2-ylmethoxy)aniline (3.5 g, 14.8 mmol, 98% yield) asa yellow solid.

170: To a solution of but-2-ynoic acid (20.0 mg, 237 umol, 9.86 uL, 3.10eq) andN4-(3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)-7-(3-morpholinopropoxy)quinazoline-4,6-diamine(40.0 mg, 76.6 umol, 1.00 eq) (obtained as intermediate V during thesynthesis of 169) in pyridine (2.00 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 613umol, 8.00 eq) and the mixture was stirred at 25° C. for 1 h. Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)−ACN]; B %:38%-58%, 10 min) to giveN-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)but-2-ynamide(10.11 mg, 17.19 umol, 22.44% yield, 100% purity) as an off-white solid.MS (ESI) m/z 588.1 [M+H] ¹H NMR (400 MHz, DMSO-d₆) δ=9.98 (br s, 1H),9.67 (s, 1H), 8.87 (d, J=1.1 Hz, 1H), 8.73-8.64 (m, 2H), 8.60 (br s,1H), 8.51 (s, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.73 (dd, J=2.4, 8.9 Hz, 1H),7.33 (d, J=9.0 Hz, 1H), 7.25 (s, 1H), 5.38 (s, 2H), 4.23 (t, J=6.1 Hz,2H), 3.60 (t, J=4.5 Hz, 4H), 2.47 (br s, 2H), 2.40 (br s, 4H), 2.07 (brs, 3H), 2.01-1.94 (m, 2H).171: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyridazin-3-ylmethoxy)aniline C.4 HNR′R″ morpholine; variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 11%overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.20-9.17 (m, 1H),9.11 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 7.94 (d, J=2.4 Hz, 1H),7.92-7.87 (m, 2H), 7.60-7.53 (m, 2H), 7.07 (d, J=8.8 Hz, 1H), 6.51-6.46(m, 2H), 5.89-5.83 (m, 1H), 5.53 (s, 2H), 4.35 (t, J=5.6 Hz, 2H),3.80-3.75 (m, 4H), 2.93 (t, J=5.6 Hz, 2H), 2.65-2.58 (m, 4H). MS (ESI)m/z 562.0 [M+H]172: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyridazin-3-ylmethoxy)aniline C.4 HNR′R″ 1-methylpiperazinevariant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 17% overall yield from XV. ¹H NMR (400 MHz, CDCl₃) δ=9.23-9.17 (m,1H), 9.14 (s, 1H), 8.91 (br s, 1H), 8.66 (s, 1H), 7.98-7.89 (m, 2H),7.67 (br s, 1H), 7.63-7.52 (m, 2H), 7.12-7.07 (m, 1H), 6.52 (br d, 1=4.4Hz, 2H), 5.91-5.84 (m, 1H), 5.56 (s, 2H), 4.37 (t, J=5.6 Hz, 2H),3.02-2.94 (m, 2H), 2.79-2.65 (m, 4H), 2.64-2.54 (m, 3H). MS (ESI) m/z575.0 [M+H]173: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyridazin-3-ylmethoxy) aniline C.4 HNR′R″8-oxa-3-azabicyclo[3.2.1]octane; hydrochloride variant ii) was used instep C.5; and variant i) was used in step C₁₋₆ and 6% overall yield fromXV. ¹H NMR (400 MHz, DMSO-4) 6 5=9.71 (s, 1H), 9.58 (s, 1H), 9.25 (dd,J=1.8, 4.9 Hz, 1H), 8.86 (s, 1H), 8.50 (s, 1H), 8.02 (d, J=2.6 Hz, 1H),7.91-7.86 (m, 1H), 7.84-7.79 (m, 1H), 7.72 (dd, J=2.6, 9.0 Hz, 1H),7.36-7.30 (m, 2H), 6.70 (dd, J=10.2, 17.1 Hz, 1H), 6.31 (dd, J=1.8, 17.0Hz, 1H), 5.87-5.79 (m, 1H), 5.53 (s, 2H), 4.32 (t, J=5.6 Hz, 2H), 4.18(br d, J=2.1 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.67 (d, J=1.5 Hz, 1H),2.65 (s, 1H), 2.33 (d, J=1.8 Hz, 1H), 2.30 (d, J=1.8 Hz, 1H), 1.85-1.76(m, 2H), 1.65 (br dd, J=3.8, 7.4 Hz, 2H). MS (ESI) m/z 588.2[M+H]⁺174: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrazin-2-ylmethoxy)aniline C.4 HNR′R″ 3-methoxyazetidinevariant ii) was used in step C.5 and variant i) was used in step C₁₋₆;and 1% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.17-9.07 (m,2H), 9.01 (s, 1H), 8.54 (s, 1H), 7.84-7.80 (m, 2H), 7.50 (dd, J=5.0, 8.4Hz, 1H), 7.44 (dd, J=2.6, 8.8 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J=8.9 Hz,1H), 6.54-6.39 (m, 2H), 5.81-5.71 (m, 1H), 5.44 (s, 2H), 4.16 (t, J=5.0Hz, 2H), 4.08 (t, J=5.6 Hz, 1H), 3.89-3.79 (m, 2H), 3.23 (s, 3H),3.21-3.14 (m, 2H), 3.06 (br t, J=4.3 Hz, 2H). MS (ESI) m/z 562.2 [M+H]⁺175: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrazin-2-ylmethoxy) aniline C.4 HNR′R″8-oxa-3-azabicyclo[3.2.1]octane variant ii) was used in step C.5; andvariant i) was used in step C₁₋₆; and 19% overall yield from XIV. ¹H NMR(400 MHz, DMSO-d₆) δ=9.70 (s, 1H), 9.56 (s, 1H), 8.92-8.81 (m, 2H),8.75-8.64 (m, 2H), 8.50 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.73 (dd,J=2.6, 8.9 Hz, 1H), 7.32 (t, J=4.5 Hz, 2H), 6.70 (dd, J=10.3, 16.9 Hz,1H), 6.32 (dd, J=1.9, 17.0 Hz, 1H), 5.86-5.77 (m, 1H), 5.38 (s, 2H),4.32 (t, J=5.6 Hz, 2H), 4.18 (br d, J=2.0 Hz, 2H), 2.79 (t, J=5.6 Hz,2H), 2.66 (br d, J=10.4 Hz, 2H), 2.32 (dd, J=1.4, 10.8 Hz, 2H),1.86-1.75 (m, 2H), 1.71-1.61 (m, 2H). MS (ESI) m/z 588.2 [M+H]⁺176: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrazin-3-ylmethoxy) aniline C.4 HNR′R″ morpholine variantii) was used in step C.5; and variant i) was used in step C₁₋₆; and 6%overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.13 (s, 1H), 9.01 (s,1H), 8.78 (br s, 1H), 8.66 (s, 1H), 8.60 (s, 2H), 7.93 (d, J=2.4 Hz,1H), 7.74 (s, 1H), 7.61-7.56 (m, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.50 (d,J=1.6 Hz, 2H), 5.92-5.84 (m, 1H), 5.34 (s, 2H), 4.37 (t, J=5.6 Hz, 2H),3.83-3.74 (m, 4H), 2.94 (t, J=5.2 Hz, 2H), 2.68-2.56 (m, 4H). MS (ESI)m/z 562.2 [M+H]⁺177: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyridazin-3-ylmethoxy) aniline C.4 HNR′R″ 3-methoxyazetidinevariant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 6% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.10 (dd,J=1.7, 5.0 Hz, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 7.85 (d,J=2.6 Hz, 1H), 7.83 (dd, J=1.7, 8.5 Hz, 1H), 7.60 (s, 1H), 7.54-7.43 (m,2H), 7.18 (s, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.49-6.39 (m, 1H), 6.36-6.27(m, 1H), 5.84-5.76 (m, 1H), 5.46 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.98(quin, J=5.8 Hz, 1H), 3.63-3.53 (m, 2H), 3.20 (s, 3H), 2.91-2.80 (m,2H), 2.62 (t, J=6.8 Hz, 2H), 1.95-1.86 (m, 2H). MS (ESI) m/z 576.5[M+H]⁺178: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrazin-3-ylmethoxy) aniline C.4 HNR′R″ 3-methoxyazetidinevariant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 9% overall yield from XIV. ¹H NMR (400 MHz, DMSO-d6) δ=9.70 (s, 1H),9.65 (s, 1H), 8.87 (d, J=1.2 Hz, 1H), 8.81 (s, 1H), 8.71-8.68 (m, 1H),8.66 (d, J=2.6 Hz, 1H), 8.50 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.73 (dd,J=2.6, 9.0 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.26 (s, 1H), 6.67 (dd,J=10.4, 17.1 Hz, 1H), 6.31 (dd, J=1.8, 17.0 Hz, 1H), 5.82 (dd, J=1.8,10.2 Hz, 1H), 5.37 (s, 2H), 4.20 (br t, J=5.1 Hz, 2H), 3.95 (quin, J=5.8Hz, 1H), 3.60 (br t, J=6.8 Hz, 2H), 3.13 (s, 3H), 2.99 (br s, 2H), 2.90(br s, 2H). MS (ESI) m/z 562.4 [M+H]⁺179: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX is3-chloro-4-(pyrazin-3-ylmethoxy) aniline C.4 HNR′R″ 1-methylpiperazinevariant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 5% overall yield from XIV. ¹H NMR (400 MHz, CDCl₃) δ=9.70 (s, 1H),9.59 (s, 1H), 8.87 (d, J=1.2 Hz, 1H), 8.86 (s, 1H), 8.71 (dd, J=1.5, 2.4Hz, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J=2.6 Hz, 1H),7.73 (dd, J=2.6, 9.0 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.25 (s, 1H), 6.72(dd, J=10.2, 16.9 Hz, 1H), 6.32 (dd, J=1.9, 16.9 Hz, 1H), 5.85-5.78 (m,1H), 5.38 (s, 2H), 4.23 (t, J=6.4 Hz, 2H), 3.95 (t, J=5.7 Hz, 1H),3.54-3.49 (m, 2H), 3.15 (s, 3H), 2.80-2.75 (m, 2H), 2.60-2.56 (m, 2H),1.87-1.80 (m, 2H). MS (ESI) m/z 576.5 [M+H]⁺180: Synthesized according to general procedure C starting fromintermediate XIII obtained in analogy to 28 wherein in step C₁₋₃ H₂NX3-chloro-4-(pyrazin-3-ylmethoxy) aniline C₁₋₄ HNR′R″ 3-methoxyazetidinevariant ii) was used in step C.5; and variant i) was used in step C₁₋₆;and 12% overall yield from XIV. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s,1H), 9.60 (s, 1H), 8.92-8.81 (m, 2H), 8.72-8.63 (m, 2H), 8.49 (s, 1H),7.99 (d, J=2.5 Hz, 1H), 7.72 (dd, J=2.6, 8.9 Hz, 1H), 7.38-7.24 (m, 2H),6.68 (dd, J=10.3, 17.0 Hz, 1H), 6.30 (dd, 1=1.9, 17.0 Hz, 1H), 5.88-5.76(m, 1H), 5.36 (s, 2H), 4.31 (t, J=5.7 Hz, 2H), 2.81 (br t, J=5.7 Hz,2H), 2.61-2.53 (m, 3H), 2.41-2.28 (m, 4H), 2.16 (s, 4H). MS (ESI) m/z575.4 [M+H]⁺

Example 2. Inhibition Activity of Exemplary Compounds of the PresentDisclosure

Retroviral Production: EGFR mutants were subcloned intopMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, Calif.).Retroviral expression vector retrovirus was produced by transienttransfection of HEK 293T cells with the retroviral EGFR mutantexpression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs),pCMV-Gag-Pol vector and pCMV-VSV-G-Envelope vector. Briefly, HEK 293T/17cells were plated in 100 mm collagen coated plate (354450, Corning LifeSciences, Tewksbury, Mass.) (4×10′ per plate) and incubated overnight.The next day, retroviral plasmids (3 pg of EGFR mutant, 1.0 pg ofpCMV-Gag-Pol and 0.5 pg pCMV-VSV-G) were mixed in 500 μl of Optimem(31985, Life Technologies). The mixture was incubated at roomtemperature for 5 min and then added to Optimem containing transfectionreagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes.Mixture was then added dropwise to HEK 293T cells. The next day themedium was replaced with fresh culture medium and retrovirus washarvested @ 24 and 48 hrs.

Generation of EGFR mutant stable cell lines. BaF3 cells (1.5E5 cells)were infected with 1 ml of viral supernatant supplemented with 8 pg/mlpolybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a37° C. incubator overnight. Cells were then spun for 5 minutes to pelletthe cells. Supernatant was removed and cells re-infected a fresh 1 ml ofviral supernatant supplemented with 8 pg/ml polybrene by centrifugingfor 30 min at 1000 rpm. Cells were placed in 37° C. incubator overnight.Cells were then maintained in RPMI containing 10% Heat Inactivated FBS,2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells wereselected for retroviral infection in 10 pg/ml Blasticidin for one week.Blasticidin resistant populations were washed twice in phosphatebuffered saline before plating in media lacking IL-3 to select for IL-3independent growth.

Assay for cell proliferation: BaF3 cell lines were resuspended at 1.3E5c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1%Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 wellplates. To determine the effect of drug on cell proliferation, cellsincubated for 3 days in the presence of vehicle control or test drug atvarying concentrations. Inhibition of cell growth was determined byluminescent quantification of intracellular ATP content usingCellTiterGlo (Promega), according to the protocol provided by themanufacturer. Comparison of cell number on day 0 versus 72 hours postdrug treatment was used to plot dose-response curves. The number ofviable cells was determined and normalized to vehicle-treated controls.Inhibition of proliferation, relative to vehicle-treated controls wasexpressed as a fraction of 1 and graphed using PRISM® software (GraphpadSoftware, San Diego, Calif.). EC₅₀ values were determined with the sameapplication.

Cellular protein analysis: Cell extracts were prepared by detergentlysis (RIPA, R0278, Sigma, St Louis, Mo.) containing 10 mM Iodoacetamide(786-228, G-Biosciences, St, Louis, Mo.), protease inhibitor (P8340,Sigma, St. Louis, Mo.) and phosphatase inhibitors (P5726, P0044, Sigma,St. Louis, Mo.) cocktails. The soluble protein concentration wasdetermined by micro-BSA assay (Pierce, Rockford Ill.). Proteinimmunodetection was performed by electrophoretic transfer of SDS-PAGEseparated proteins to nitrocellulose, incubation with antibody, andchemiluminescent second step detection. Nitrocellulose membranes wereblocked with 5% nonfat dry milk in TBS and incubated overnight withprimary antibody in 5% bovine serum albumin. The following primaryantibodies from Cell Signaling Technology were used at 1:1000 dilution:phospho-EGFR[Y1173] and total EGFR. p-Actin antibody, used as a controlfor protein loading, was purchased from Sigma Chemicals. Horseradishperoxidase-conjugated secondary antibodies were obtained from CellSignaling Technology and used at 1:5000 dilution. Horseradishperoxidase-conjugated secondary antibodies were incubated in nonfat drymilk for 1 hour. SuperSignal chemiluminescent reagent (PierceBiotechnology) was used according to the manufacturer's directions andblots were imaged using the Alpha Innotech image analyzer andAlphaEaseFC software (Alpha Innotech, San Leandro Calif.).

Tables A and B assign each compound a potency code: A, B, C, D, E, F, G,H, I, J or K.

According to the code, A represents an IC50 value ≤5 nM. B represents anIC50 value >5 nM and ≤10 nM. C represents an IC50 value >10 nM and ≤20nM. D represents an IC50 value >20 nM and ≤30 nM. E represents an IC50value >30 nM and ≤50 nM. F represents an IC50 value >50 nM and ≤100 nM.G represents an IC50 value >100 nM and ≤200 nM. H represents an IC50value >200 nM and ≤300 nM. I represents an IC50 value >300 nM and ≤500nM. J represents an IC50 value >500 nM and ≤1000 WM K represents an IC50value >1000 nM.

TABLE A Activity for Inhibiting EGFR Compound No. EGFR WT EGFR V3 EGFRNPH EGFR SVD 1 K G 2 K F 3 I E 4 H F 5 E C E C 6 H D 7 K G 8 I D E D 9 JF 10 K F 11 I F I I 12 J G 13 I F I H 14 I E 15 I H 16 H D 17 H C D C 18I D 19 H D G G 20 H D C C 21 J D C C 22 F D D C 23 K G 24 K H 25 J H D E26 I E E E 27 I E 28 H C F E 29 I D 30 I E 31 J E F F 32 I D 33 I D F F34 J E 35 I D F D 36 K E F F 37 K G 38 I E 39 J D F E 40 H C C C 41 J EF E 42 J F K J 43 K G 44 I G 45 J H 46 I F 47 I E J J 48 K H 49 K G 50 KE 51 J D F E 52 J D F F 53 K E 54 K C G F 55 K F 56 I D I I 57 J C F E58 K H 59 I E 60 H C H H 61 K I 62 I C E D 63 K F I I 64 K G 65 J D 66 JD G F 67 G D 68 J G J J 69 I C D D 70 F C F E 71 J F 72 K I 73 J F 74 KF 75 K G 76 H F 77 G F 78 K E I H 79 I F 80 G F 81 H G 82 J I 83 J F 84J D F F 85 H D D D 86 J G 87 K G 88 J E 89 F E 90 J E 91 J F 92 G E 93 KH 94 I E 95 G D 96 G C 97 J F 98 H E 99 H D 100 I E 101 G C 102 J E F E103 H E 104 D E 105 J F 106 G E 107 H F 108 J G 109 E C 110 H D 111 I E112 I G 113 J F 114 I E 115 H E 116 J E 117 J G 118 H D 119 I F 120 K E121 K G 122 J F 123 H E 124 J E 125 J G 126 I E 127 J F 128 J G 129 J G130 H G 131 H G 132 K I 133 H G 134 H F 135 I F 136 G G 137 H F 138 G F139 J G 140 I G 141 G G 142 J G 143 H F 144 G G 145 G F 146 F F 147 J F148 H G 149 G F 150 H F 151 G F 152 G E 153 J E 154 J E 155 I E 156 K F157 J E 158 G E 159 I G 160 I G 161 H E 162 I E 163 K F 164 I F 165 G E166 K E 167 K E 168 H E 169 K E 170 H E 171 K F 172 J G 173 K F 174 K F175 K E 176 K E 177 J E 178 K E 179 J E 180 J E

TABLE B Activity for Inhibiting HER2 Compound No. HER2 WT HER2 S310FHER2 YVMA 1 F J 2 G I 3 C D 4 D F 5 A A B 6 B C F 7 G H 8 B C F 9 C G 10C D H 11 E F 12 F G 13 B E I 14 C F 15 C G 16 A D E 17 A B E 18 B D F 19B D G 20 A C C 21 A B D 22 A B E 23 G G 24 H I 25 C C F 26 B B E 27 C DE 28 B C E 29 A C F 30 A C G 31 B E G 32 A C F 33 B C G 34 C C F 35 A CE 36 C D E 37 F F 38 B D F 39 B C F 40 A C D 41 B D F 42 E F J 43 F G 44F I 45 I K 46 D G 47 C E J 48 G I 49 F G 50 H K 51 B C F 52 B D G 53 E G54 B D G 55 F H 56 D F H 57 B C F 58 G I 59 E G 60 B D I 61 I K 62 A B E63 E F I 64 I K 65 C C F 66 F C F 67 B C F 68 C E I 69 C D 70 B B 71 H K72 I K 73 E I 74 G H 75 G I 76 E G 77 D G 78 C F J 79 G K 80 F J 81 G K82 F J 83 C G 84 B E 85 B E 86 D G 87 E H 88 C G 89 C F 90 D G 91 E H 92D G 93 J K 94 E I 95 B E 96 C H 97 H J 98 D H 99 E H 100 F I 101 C E 102D F 103 C F 104 E E 105 E G 106 E G 107 C E 108 F J 109 C F 110 E H 111E G 112 I K 113 E G 114 E G 115 E F 116 E H 117 F G 118 C D 119 F G 120C F 121 E I 122 G J 123 E G 124 E G 125 G K 126 E F 127 I K 128 G I 129E G 130 E I 131 F I 132 I J 133 F J 134 E I 135 G I 136 E G 137 F I 138E F 139 E G 140 G I 141 E I 142 I K 143 E G 144 E G 145 E H 146 D F 147F H 148 D F 149 C E 150 C E 151 C G 152 B F 153 C F 154 E G 155 C E 156E H 157 E I 158 E G 159 F I 160 G I 161 E G 162 E G 163 E G 164 E G 165C F 166 E G 167 C F 168 D F 169 C E 170 B C 171 F I 172 F I 173 E H 174F I 175 D G 176 D G 177 C F 178 E G 179 C E 180 D G

Example 3. Selective Targeting of Various HER and EGFR Mutants

To determine the ability of Compound No. 6 to target wild type HER2,wild type EGFR, and relevant mutants of each, a panel of BaF3 cell linesand the A431 cell line were dosed and assessed in cell proliferationassays. The BaF3 parental cell line is normally dependent on IL-3 forproliferation, but when transformed with active tyrosine kinase can growin the absence of IL-3. However, when transformed kinase activity isinhibited by a targeted small molecule the associated proliferation isreduced in proportion to the extent of inhibition. A panel of BaF3 celllines were generated by transforming the parental BaF3 cell line withwild type HER-2 (HER2-WT), HER2 S310F (HER2-S310F), HER2 Exon 20insertion YVMA (HER2-YVMA), EGFR-Exon 20 insertion ASV (EGFR-ASV),EGFR-Exon 20 insertion SVD (EGFR-SVD), or EGFR-Exon 20 insertion NPH(EGFR-NPH). The A431 lung cancer cell line, which natively expressesWT-EGFR, was used to assess WT-EGFR inhibition. To perform theproliferation assays, cells were plated in 96-well plates and subjectedto various doses of Compound No. 6 to generate a dose-response curve foreach cell line. Proliferation was assessed using the Cell Titer Glo cellproliferation kit (Promega #G7573). Briefly, Cell Titer Glo reagent wasthawed and allowed to equilibrate at room temperature for 30 minutes.Plated and dosed cells were also allowed to equilibrate at RoomTemperature for 30 minutes. Cell Titer Glo was added to plated cells at15 ul per well, the plate was shaken for 20 minutes at room temperature,and luminescence was measured using Victor X3 Multimode plate reader(Perkin Elmer). Cell Titer Glo readings were taken following 72 hours(T72) after addition of Compound No. 6. Dose-response curves weregenerated for each cell line and IC50 values generated (FIG. 21). Asshown in FIG. 21, compound No. 6 has the highest potency for HER-WT withan IC50 value <10 nM. Compound No. 6 has relatively high potency againstHER2-S10F, HER2-ASV, EGFR-SVD, and EGFR-NPH, with IC50 values: 100 nM.Compound No. 6 showed reduced potency against EGFR-WT, with an IC50value >100 nM. These results indicate that Compound No. 6 targets andinhibits wild type HER2 and a variety of clinically relevant HER2 andEGFR mutants, but largely spares wild type EGFR in a cellular model.

Example 4. Inhibition of Proliferation in Patient-Derived Cell Lines

Compound No. 6 inhibition of EGFR-NPH and EGFR-ASV mutants inpatient-derived cell lines was assessed using cell proliferation assays.The CUTO-14 and CUTO-17 cellular models are patient-derived cell linesthat natively express the EGFR-ASV and EGFR-NPH mutants, respectively.The EGFR-WT expressing A431 cell line was used as a reference in theassessment. To perform the proliferation assays, cells were plated in96-well plates and subject dose-response curves using Compound No. 6.Proliferation was assessed using the Cell Titer Glo cell proliferationkit (Promega #G7573). Briefly, Cell Titer Glo reagent was thawed andallowed to equilibrate at room temperature for 30 minutes. Plated anddosed cells were also allowed to equilibrate at Room Temperature for 30minutes. Cell Titer Glo was added to plated cells at 15 ul per well, theplate was shaken for 20 minutes at room temperature, and luminescencewas measured using Victor X3 Multimode plate reader (Perkin Elmer). CellTiter Glo readings were taken following 72 hours (T72) after addition ofCompound No. 6. The CUTO-14 (EGFR-ASV) and CUTO-17 (EGFR-NPH) cell linesresponded comparably to Compound No. 6 as the BaF3 transformants,showing similar IC50 values (FIG. 22), indicating that Compound No. 6selectively inhibits particular EGFR mutants, including EGFR-NPH andEGFR-ASV.

Example 5. Selective Inhibition of EGFR Mutants

A shown in the top panel of FIG. 23, marketed compounds that target EGFRmutants show off-target binding to wild type EGFR, resulting intoxicities and reduced efficacy (FIG. 23, top panel). To determine therelative selectivity of Compound No. 8 for targeting EGFR mutants overwild type EGFR, the patient-derived CUTO-14 and CUTO-17 cellular modelsthat natively express EGFR-ASV and EGFR-NPH mutants, respectively, weredosed with Compound No. 8 over a range of concentrations. Followingdosing, the cells were assessed for EGFR mutant signaling and cellproliferation. To measure signaling, the pERK AlphaLisa (Perkin Elmer#ALSU-PERK-A10K) was used to quantify phosphorylation of ERK1/2(Thr202/Tyr204) in all treated cells. Cell proliferation was determinedusing the Cell Titer Glo assay (Promega #G7573) at 72 hours followingtreatment. IC50 values for both pERK and growth inhibition (GI50) weredetermined (FIG. 23, bottom table). The GI50 values calculated forCompound No. 8 in CUTO-14 and CUTO-17 cells were used to assess relativeselectivity with reference to the GI50 value generated in Compound No. 8treated A431 cells for EGFR-WT (FIG. 23, bottom table). The ratio of theGI50 value in A431 cells to the GI50 in CUTO-14 and the ratio of theGI50 value in A431 cells to the GI50 in CUTO-17 was calculated (FIG. 23,bottom table). Higher ratios represent higher selectivity for the EGFRmutants compared to EGFR-WT. The ratios were compared to referencevalues for marketed EGFR inhibitors, and the results indicate thatCompound No. 8 has reduced off-target binding to EGFR-WT relative to themarketed inhibitors.

Example 6. Selective Targeting of Various HER and EGFR Mutants

To determine the ability of Compound No. 8 to target wild type HER2,wild type EGFR, and clinically relevant mutants of each, a panel of BaF3cell lines and the A431 cell line were dosed and assessed in cellproliferation assays. The BaF3 parental cell line is normally dependenton IL-3 for proliferation, but when transformed with active tyrosinekinase can grow in the absence of IL-3. However, when transformed kinaseactivity is inhibited by a targeted small molecule the associatedproliferation is reduced in proportion to the extent of inhibition. Apanel of BaF3 cell lines were generated by transforming the parentalBaF3 cell line with wild type HER2, EGFR-19DEL, EGFR-L858R, HER2-A232V,HER2-S310F, HER2-P95, HER2-R678Q, HER2-L755S, HER2-V777L, HER2-YVMA,HER2-GSP, EGFR-NPH, EGFR-SVD, EGFR-ASV, EGFR-FQEA. The A431 and H292cell lines, which natively express WT-EGFR, were used to assess WT-EGFRinhibition. The CUTO-14 and CUTO-17 patient-derived cellular models thatnatively express the EGFR-ASV and EGFR-NPH mutants, respectively, werealso included in the panel. To perform the proliferation assays, cellswere plated in 96-well plates and subjected to various doses of CompoundNo. 8 to generate a dose-response curve for each cell line.Proliferation was assessed using the Cell Titer Glo cell proliferationkit (Promega #G7573). Briefly, Cell Titer Glo reagent was thawed andallowed to equilibrate at room temperature for 30 minutes. Plated anddosed cells were also allowed to equilibrate at Room Temperature for 30minutes. Cell Titer Glo was added to plated cells at 15 ul per well, theplate was shaken for 20 minutes at room temperature, and luminescencewas measured using Victor X3 Multimode plate reader (Perkin Elmer). CellTiter Glo readings were taken following 72 hours (T72) after addition ofCompound No. 8. Dose-response curves were generated for each cell lineand IC50 values generated (FIG. 24). The results show that Compound No.8 has the high potency for HER-WT and all mutants, with IC50 values <100nM. In contrast, Compound No. 8 showed reduced potency against EGFR-WT,with an IC50 value >100 nM in A431 and H292 cells. These resultsindicate that Compound No. 8 targets and inhibits wild type HER2 and avariety of clinically relevant HER2 and EGFR mutants, but largely spareswild type EGFR in a cellular model.

Example 7. Inhibition of Kinase Targets In Vivo in Allo-ErbB MutantTumor Models

The ability of Compound No. 8 to target and inhibit HER2 and EGFR mutantactivity in vivo was tested using mouse models containing relevant tumorxenotransplantations. The xenotransplant mice were administered CompoundNo. 8 and tumors were collected and analyzed for phosphositesrepresentative of Her2 or EGFR signaling. Athymic nude mice from CharlesRiver Labs bearing either Her2 Exon 20-YVMA A775, or Her2 S310F, orEGFR-Viii BaF3 tumors were treated with two day acute oral dosing ofCompound No. 8 at 50 mg/kg. Following the second dose, tumors werecollected at 2 hours, 5 hours, and 24 hours. The tumor tissue was cutand homogenized using the Precellys Soft Tissue Homogenizing kit(KT03961-1-00.3.2) containing T-PER tissue protein extraction reagent(Thermo Scientific #78510), supplemented with Protease Inhibitor (SigmaP8340), and Phosphatase Inhibitors II and III (Sigma P5726 and P0044).Tissue samples were homogenized in the Precellys machine by spinning twotimes for one minute each. Sample tubes were centrifuged for 5 min at15,000 rpm at 4° C. The supernatant was transferred to a fresh microtubeand spun again for 5 minutes at 15,000 rpm at 4° C. Supernatant was thentransferred to a fresh microtube and placed on ice. The proteinconcentration of the supernatant was measured using the BCA reagent Kit(Thermo Scientific #23225). Tumor tissue-derived lysates were analyzedfor either HER2 activity or EGFR activity by detection of pErbB2(Tyr1221/1222) or pERK (Thr202/Tyr204) phosphosites, respectively, viaAlphaLisa. Briefly, tumor Lysates were diluted to 0.5 ug/ul in 1×diluted SureFire Ultra Kit Lysis Buffer (5× supplied stock) supplementedwith Protease Inhibitor (Sigma P8340) and Phosphatase Inhibitor II andIII (Sigma P5726 and P0044). 10 ul of total tumor lysate was added perwell in triplicate to a 384-well Opti-plate (Perkin Elmer #6007290).Activation Buffer was diluted 25-fold in combined Reaction Buffer 1 andReaction Buffer 2, and acceptor beads were diluted 50-fold in thecombined Reaction Buffers. 5 ul/well of the Acceptor bead:Reactionbuffer mixture was added to each well. The plate was covered and shakenfor 5 minutes on a plate shaker and then incubated at room temperaturein the dark for 90 minutes before reading. As shown in FIG. 25, asignificant reduction in the abundance of phosphorylation of both theHER2 and ERK-related phosphosites occurred following the treatmentprotocol indicating that Compound No. 8 inhibits HER2 and EGFR activityin vivo.

Example 8. Tumor Growth Inhibition in Mice Bearing Her2 Mutant Tumors

A mouse tumor model containing mutant Her2 was used to test Compound No.8's ability to inhibit tumor growth and induce tumor regression in vivo.Athymic nude mice from Charles River Labs bearing Her2 S310F BaF3 tumorswere treated with Compound No. 8 either at 50 mg/kg once per day for 10days or in a dose-dependent manner ranging from 15 mg/kg to 100 mg/kgonce per day (QD) for 10 days. Tumor size was measured for each dosingschedule, and analyzed to assess regression. For the 50 mg/kg CompoundNo. 8 10-day dosing, tumor size was observed over the 10-day timecourseas shown in the left panel of FIG. 26. Tumor volume in the vehiclecontrol increased over the 10 days whereas the tumor volume in micedosed with Compound No. 8 decreased over the same timeframe, indicatingthat Compound No. 8 induces regression in tumors harboring the Her2S310F mutation. The effect was further confirmed in the dose-dependentexperiment. The tumor regressed in a Compound No. 8 dose-dependentmanner as shown in the right panel of FIG. 26. These results demonstratethat Compound No. 8 induces tumor growth inhibition and tumor regressionin vivo, including in tumors harboring the Her2 S310F mutation.

Example 9. Tumor Growth Inhibition in Mice Bearing HER2 Mutant Tumors

A mouse tumor model containing mutant Her2 was used to test the abilityof Compound No. 26 to inhibit tumor growth and induce tumor regressionin vivo. Athymic nude mice from Charles River Labs bearing Her2 S310FBaF3 tumors were treated with Compound No. 26 either at 15 mg/kg onceper day (QD), 7.5 mg/kg twice per day (BID), and 15 mg/kg twice per day(BID). Tumor size was measured for each dosing condition and analyzed toassess regression. As shown in FIG. 27, tumor volume in the vehiclecontrol increased over the timecourse, whereas the tumor volume in micedosed with Compound No. 26 did not increase over the same timeframe,indicating that Compound No. 26 prevents growth in tumors harboring theHer2 S310F mutation. The effect was further confirmed in mice dosed at15 mg/kg once per day (QD), 7.5 mg/kg twice per day (BID), and 15 mg/kgtwice per day (BID). In addition to assessing tumor size in thesegroups, plasma was collected from dosed individuals at 2 and 5 hoursfollowing each treatment. Compound No. 26 levels were measured in theplasma samples to determine pharmacokinetic profiles that may influencetumor response. As shown in the right panel of FIG. 28, peak plasmalevels were found in mice dosed with 15 mg/kg BID, which was the groupwith the highest number of individuals in which tumor regressions wereobserved. As shown in the left panel of FIG. 28, the 15 mg/kg once perday (QD) and 7.5 mg/kg twice per day (BID) dosing groups showed definitetumor growth inhibition properties, while the 15 mg/kg BID dosing groupshowed definite tumor regressive properties. These results demonstratethat Compound No. 26 prevents tumor growth and induces tumor regressionin vivo, including in tumors harboring the Her2 S310F mutation.

Example 10. Tumor Growth Inhibition in Mice Bearing HER2 Mutant Tumors

A mouse tumor model containing mutant Her2 was used to test the abilityof Compound No. 21 to inhibit tumor growth and induce tumor regressionin vivo. Athymic nude mice from Charles River Labs bearing Her2 S310FBaF3 tumors were treated with Compound No. 21 at 50 mg/kg once per day(QD) for 10 days. Tumor size was measured and analyzed to assess theeffect on tumor growth and regression. As shown in FIG. 29, tumor volumein the vehicle control experiments increased over the 10-day timecourse,whereas the tumor volume in mice dosed with Compound No. 21 did notincrease over the same timeframe and showed moderate reduction involume, indicating that Compound No. 21 prevents growth and inducesmoderate regression in tumors harboring the Her2 S310F mutation. Theseresults demonstrate that Compound No. 21 prevents tumor growth andinduces tumor regression in vivo, including in tumors harboring the Her2S310F mutation.

Example 11. Tumor Growth Inhibition in Mice Bearing HER2 Mutant Tumors

A mouse tumor model containing mutant Her2 was used to test the abilityof Compound No. 6 to inhibit tumor growth and induce tumor regression invivo. Athymic nude mice from Charles River Labs bearing Her2 S310F BaF3tumors were treated with Compound No. 6 at 30 mg/kg once per day (QD)for 10 days. Tumor size was measured and analyzed to assess the effecton tumor growth and regression. As shown in FIG. 30, tumor volume in thevehicle control experiments increased over the 10-day timecourse,whereas the tumor volume in mice dosed with Compound No. 6 decreasedover the same time, indicating that Compound No. 6 induces regression intumors harboring the Her2 S310F mutation. These results demonstrate thatCompound No. 6 prevents tumor growth and induces tumor regression invivo, including in tumors harboring the Her2 S310F mutation.

Example 12. Tumor Growth Inhibition in Mice Bearing EGFR Mutant Tumors

To determine the ability of Compound No. 8 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing theEGFR-Exon 20 insertion ASV (CUTO-14) mutation was used. Athymic nudemice from Charles River Labs bearing CUTO-14 tumors were treated withCompound No. 8 at either 30 mg/kg once per day (QD) or 50 mg/kg twiceper 30 day (BID) over the indicated time course, and tumor volume wasmeasured. Tumor volume was analyzed to assess the effect of Compound No.8 on tumor growth and regression. As shown in FIG. 31, tumor volume inthe vehicle control experiments increased over the timecourse, whereasthe tumor volume in mice dosed with either the 30 mg/kg QD Compound No.8 or the 50 mg/kg BID Compound No. 8 dosing schemes decreased over thesame time. These results demonstrate that Compound No. 8 induces tumorgrowth inhibition and tumor growth regression in vivo, including intumors harboring the EGFR-Exon 20 insertion ASV mutation.

Example 13. Tumor Growth Inhibition in Mice Bearing EGFR Mutant Tumors

To determine the ability of Compound No. 6 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing theEGFR-Exon 20 insertion ASV (CUTO-14) mutation was used. Athymic nudemice from Charles River Labs bearing CUTO-14 tumors were treated withCompound No. 6 at either 50 mg/kg once per day (QD) or 25 mg/kg twiceper day (BID) over the indicated time course, and tumor volume wasmeasured. Tumor volume was analyzed to assess the effect of Compound No.6 on tumor growth and regression. As shown in FIG. 32, tumor volume inthe vehicle control experiments increased over the timecourse, whereasthe tumor volume in mice dosed with either the 50 mg/kg QD Compound No.6 or the 25 mg/kg BID Compound No. 6 dosing schemes decreased over thesame time. These results demonstrate that Compound No. 6 induces tumorgrowth inhibition and tumor regression in vivo, including in tumorsharboring the EGFR-Exon 20 insertion ASV mutation.

Example 14. Inhibition of HER2 Activity in Mice Bearing Her2 MutantTumors

To determine the ability of Compound No. 21 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing the HER2Exon 20-YVMA A775 mutation was used. Athymic nude mice from CharlesRiver Labs bearing Her2 Exon 20-YVMA A775 BaF3 tumors were treated withtwo day acute oral dosing of Compound No. 26 at 15 mg/kg. Following thesecond dose, tumors were collected at 2 hours, 5 hours, 12 hours and 24hours, and analyzed for both pHER2 activity and pERK activity viaAlphaLisa. Plasma was also collected at these time points and analyzedfor the presence of Compound No. 26 to determine pharmacokineticprofile. The tumor tissue was cut and homogenized using the PrecellysSoft Tissue Homogenizing kit (KT03961-1-00.3.2) containing T-PER tissueprotein extraction reagent (Thermo Scientific #78510), supplemented withProtease Inhibitor (Sigma P8340), and Phosphatase Inhibitors II and III(Sigma P5726 and P0044). Tissue samples were homogenized in thePrecellys machine by spinning two times for one minute each. Sampletubes were centrifuged for 5 min at 15,000 rpm at 4° C. The supernatantwas transferred to a fresh microtube and spun again for 5 minutes at15,000 rpm at 4° C. Supernatant was then transferred to a freshmicrotube and placed on ice. The protein concentration of thesupernatant was measured using the BCA reagent Kit (Thermo Scientific#23225). Tumor tissue-derived lysates were analyzed for either HER2activity or EGFR activity by detection of pHER2 (Tyr1221/1222) or pERK(Thr202/Tyr204) phosphosites, respectively, via AlphaLisa. Briefly,tumor Lysates were diluted to 0.5 ug/ul in 1× diluted SureFire Ultra KitLysis Buffer (5× supplied stock) supplemented with Protease Inhibitor(Sigma P8340) and Phosphatase Inhibitor II and III (Sigma P5726 andP0044). 10 ul of total tumor lysate was added per well in triplicate toa 384-well Opti-plate (Perkin Elmer #6007290). Activation Buffer wasdiluted 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2, andacceptor beads were diluted 50-fold in the combined Reaction Buffers. 5ul/well of the Acceptor bead:Reaction buffer mixture was added to eachwell. The plate was covered and shaken for 5 minutes on a plate shakerand then incubated at room temperature in the dark for 90 minutes beforereading. pHer2 AlphaLisa (Perkin Elmer # ALSU-PEB2-A10K) was used toquantify phosphorylation of Her2 (Tyr1221/1222) or pERK AlphLisA (PerkinElmer #ALSUPERK-A10K) was used to quantify phosphorylation of ERK1/2(Thr202/Tyr204) in the control and Compound No. 26 treated tumorsamples. As shown in FIG. 33, Compound No. 26 induced a near completereduction of pHER2 and pERK1/2 at peak plasma levels, indicating thatCompound No. 26 inhibits target mutant Her2 Exon 20-YVMA A775 kinaseactivity.

Example 15. Treatment of Mice Bearing HER2 Mutant Tumors

To determine the ability of Compound No. 21 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing the HER2S310F mutation was used to determine whether Compound No. 21. Athymicnude mice from Charles River Labs bearing HER2 S310F BaF3 tumors weretreated with two day acute oral dosing of Compound No. 21 at 15 mg/kg.Following the second dose, tumors were collected at 2 hours, 5 hours, 12hours and 24 hours, and analyzed for both pHER2 activity and pERKactivity via AlphaLisa. Plasma was also collected at these time pointsand analyzed for the presence of Compound No. 21 to determinepharmacokinetic profile. The tumor tissue was cut and homogenized usingthe Precellys Soft Tissue Homogenizing kit (KT03961-1-00.3.2) containingT-PER tissue protein extraction reagent (Thermo Scientific #78510),supplemented with Protease Inhibitor (Sigma P8340), and PhosphataseInhibitors II and III (Sigma P5726 and P0044). Tissue samples werehomogenized in the Precellys machine by spinning two times for oneminute each. Sample tubes were centrifuged for 5 min at 15,000 rpm at 4°C. The supernatant was transferred to a fresh microtube and spun againfor 5 minutes at 15,000 rpm at 4° C. Supernatant was then transferred toa fresh microtube and placed on ice. The protein concentration of thesupernatant was measured using the BCA reagent Kit (Thermo Scientific#23225). Tumor tissue-derived lysates were analyzed for either HER2activity or EGFR activity by detection of pHER2 (Tyr1221/1222) or pERK(Thr202/Tyr204) phosphosites, respectively, via AlphaLisa. Briefly,tumor Lysates were diluted to 0.5 ug/ul in 1× diluted SureFire Ultra KitLysis Buffer (5× supplied stock) supplemented with Protease Inhibitor(Sigma P8340) and Phosphatase Inhibitor II and III (Sigma P5726 andP0044). 10 ul of total tumor lysate was added per well in triplicate toa 384-well Opti-plate (Perkin Elmer #6007290). Activation Buffer wasdiluted 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2, andacceptor beads were diluted 50-fold in the combined Reaction Buffers. 5ul/well of the Acceptor bead:Reaction buffer mixture was added to eachwell. The plate was covered and shaken for 5 minutes on a plate shakerand then incubated at room temperature in the dark for 90 minutes beforereading. pHer2 AlphaLisa (Perkin Elmer # ALSU-PEB2-A10K) was used toquantify phosphorylation of Her2 (Tyr1221/1222) or pERK AlphLisA (PerkinElmer #ALSUPERK-A10K) was used to quantify phosphorylation of ERK1/2(Thr202/Tyr204) in the control and Compound No. 21 treated tumorsamples. As shown in FIG. 34, Compound No. 21 induced a near completereduction of pHER2 and pERK1/2 at peak plasma levels, indicating thatCompound No. 21 inhibits target HER2 S310F mutant kinase activity.

Example 16. Treatment of Mice Bearing HER2 Mutant Tumors

To determine the ability of Compound No. 5 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing the HER2S310F mutation was used to determine whether Compound No. 5 inhibitstumor growth and induces tumor regression in vivo. Athymic nude micefrom Charles River Labs bearing HER2 S310F BaF3 tumors were treated withtwo day acute oral dosing of Compound No. 5 at 15 mg/kg. Following thesecond dose, tumors were collected at 2 hours, 5 hours, 12 hours and 24hours, and analyzed for both pHER2 activity and pERK activity viaAlphaLisa. Plasma was also collected at these time points and analyzedfor the presence of Compound No. 5 to determine pharmacokinetic profile.The tumor tissue was cut and homogenized using the Precellys Soft TissueHomogenizing kit (KT03961-1-00.3.2) containing T-PER tissue proteinextraction reagent (Thermo Scientific #78510), supplemented withProtease Inhibitor (Sigma P8340), and Phosphatase Inhibitors II and III(Sigma P5726 and P0044). Tissue samples were homogenized in thePrecellys machine by spinning two times for one minute each. Sampletubes were centrifuged for 5 min at 15,000 rpm at 4° C. The supernatantwas transferred to a fresh microtube and spun again for 5 minutes at15,000 rpm at 4° C. Supernatant was then transferred to a freshmicrotube and placed on ice. The protein concentration of thesupernatant was measured using the BCA reagent Kit (Thermo Scientific#23225). Tumor tissue-derived lysates were analyzed for either HER2activity or EGFR activity by detection of pHER2 (Tyr1221/1222) or pERK(Thr202/Tyr204) phosphosites, respectively, via AlphaLisa. Briefly,tumor Lysates were diluted to 0.5 ug/ul in 1× diluted SureFire Ultra KitLysis Buffer (X supplied stock) supplemented with Protease Inhibitor(Sigma P8340) and Phosphatase Inhibitor II and III (Sigma P5726 andP0044). 10 ul of total tumor lysate was added per well in triplicate toa 384-well Opti-plate (Perkin Elmer #6007290). Activation Buffer wasdiluted 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2, andacceptor beads were diluted 50-fold in the combined Reaction Buffers. 5ul/well of the Acceptor bead:Reaction buffer mixture was added to eachwell. The plate was covered and shaken for 5 minutes on a plate shakerand then incubated at room temperature in the dark for 90 minutes beforereading. pHer2 AlphaLisa (Perkin Elmer # ALSU-PEB2-A10K) was used toquantify phosphorylation of Her2 (Tyr1221/1222) or pERK AlphLisA (PerkinElmer # ALSUPERK-A10K) was used to quantify phosphorylation of ERK1/2(Thr202/Tyr204) in the control and Compound No. 5 treated tumor samples.As shown in FIG. 35, Compound No. 5 induced The a reduction of pHER2 andpERK1/2 at peak plasma levels, indicating that Compound No. 5 inhibitstarget HER2 S310F mutant kinase activity.

Example 17. Treatment of Mice Bearing HER2 Mutant Tumors

To determine the ability of Compound No. 118 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing the HER2S310F mutation was used. Athymic nude mice from Charles River Labsbearing HER2 S310F BaF3 tumors were treated with two day acute oraldosing of Compound No. 118 at 15 mg/kg. Following the second dose,tumors were collected at 2 hours, 5 hours, 12 hours and 24 hours, andanalyzed for both pHER2 activity and pERK activity via AlphaLisa. Plasmawas also collected at these time points and analyzed for the presence ofCompound No. 118 to determine pharmacokinetic profile. The tumor tissuewas cut and homogenized using the Precellys Soft Tissue Homogenizing kit(KT03961-1-00.3.2) containing T-PER tissue protein extraction reagent(Thermo Scientific #78510), supplemented with Protease Inhibitor (SigmaP8340), and Phosphatase Inhibitors II and III (Sigma P5726 and P0044).Tissue samples were homogenized in the Precellys machine by spinning twotimes for one minute each. Sample tubes were centrifuged for 5 min at15,000 rpm at 4° C. The supernatant was transferred to a fresh microtubeand spun again for 5 minutes at 15,000 rpm at 4° C. Supernatant was thentransferred to a fresh microtube and placed on ice. The proteinconcentration of the supernatant was measured using the BCA reagent Kit(Thermo Scientific #23225). Tumor tissue-derived lysates were analyzedfor either HER2 activity or EGFR activity by detection of pHER2(Tyr1221/1222) or pERK (Thr202/Tyr204) phosphosites, respectively, viaAlphaLisa. Briefly, tumor Lysates were diluted to 0.5 ug/ul in 1×diluted SureFire Ultra Kit Lysis Buffer (5× supplied stock) supplementedwith Protease Inhibitor (Sigma P8340) and Phosphatase Inhibitor II andIII (Sigma P5726 and P0044). 10 ul of total tumor lysate was added perwell in triplicate to a 384-well Opti-plate (Perkin Elmer #6007290).Activation Buffer was diluted 25-fold in combined Reaction Buffer 1 andReaction Buffer 2, and acceptor beads were diluted 50-fold in thecombined Reaction Buffers. 5 ul/well of the Acceptor bead:Reactionbuffer mixture was added to each well. The plate was covered and shakenfor 5 minutes on a plate shaker and then incubated at room temperaturein the dark for 90 minutes before reading. pHer2 AlphaLisa (Perkin Elmer# ALSU-PEB2-A10K) was used to quantify phosphorylation of Her2(Tyr1221/1222) or pERK AlphLisA (Perkin Elmer # ALSUPERK-A10K) was usedto quantify phosphorylation of ERK1/2 (Thr202/Tyr204) in the control andCompound No. 118 treated tumor samples. As shown in FIG. 36, CompoundNo. 118 induced a reduction of pHER2 and pERK1/2 at peak plasma levels,indicating that Compound No. 118 inhibits target HER2 S310F mutantkinase activity.

Example 18. Treatment of Mice Bearing HER2 Mutant Tumors

To determine the ability of Compound No. 27 to inhibit tumor growth andinduce tumor regression in vivo, a mouse tumor model containing theHER2S310F mutation was used. Athymic nude mice from Charles River Labsbearing HER2 S310F BaF3 tumors were treated with two day acute oraldosing of Compound No. 27 at 15 mg/kg. Following the second dose, tumorswere collected at 2 hours, 5 hours, 12 hours and 24 hours, and analyzedfor both pHER2 activity and pERK activity via AlphaLisa. Plasma was alsocollected at these time points and analyzed for the presence of CompoundNo. 27 to determine a pharmacokinetic profile of the compound. The tumortissue was cut and homogenized using the Precellys Soft TissueHomogenizing kit (KT03961-1-00.3.2) containing T-PER tissue proteinextraction reagent (Thermo Scientific #78510), supplemented withProtease Inhibitor (Sigma P8340), and Phosphatase Inhibitors II and III(Sigma P5726 and P0044). Tissue samples were homogenized in thePrecellys machine by spinning two times for one minute each. Sampletubes were centrifuged for 5 min at 15,000 rpm at 4° C. The supernatantwas transferred to a fresh microtube and spun again for 5 minutes at15,000 rpm at 4° C. Supernatant was then transferred to a freshmicrotube and placed on ice. The protein concentration of thesupernatant was measured using the BCA reagent Kit (Thermo Scientific#23225). Tumor tissue-derived lysates were analyzed for either HER2activity or EGFR activity by detection of pHER2 (Tyr1221/1222) or pERK(Thr202/Tyr204) phosphosites, respectively, via AlphaLisa. Briefly,tumor Lysates were diluted to 0.5 ug/ul in 1× diluted SureFire Ultra KitLysis Buffer (5× supplied stock) supplemented with Protease Inhibitor(Sigma P8340) and Phosphatase Inhibitor II and III (Sigma P5726 andP0044). 10 ul of total tumor lysate was added per well in triplicate toa 384-well Opti-plate (Perkin Elmer #6007290). Activation Buffer wasdiluted 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2, andacceptor beads were diluted 50-fold in the combined Reaction Buffers. 5ul/well of the Acceptor bead:Reaction buffer mixture was added to eachwell. The plate was covered and shaken for 5 minutes on a plate shakerand then incubated at room temperature in the dark for 90 minutes beforereading. pHer2 AlphaLisa (Perkin Elmer # ALSU-PEB2-A10K) was used toquantify phosphorylation of Her2 (Tyr1221/1222) or pERK AlphLisA (PerkinElmer #ALSUPERK-A10K) was used to quantify phosphorylation of ERK1/2(Thr202/Tyr204) in the control and Compound No. 27 treated tumorsamples. As shown in FIG. 37, treatment with Compound No. 27 induced areduction of pHER2 and pERK1/2 at peak plasma levels, indicating thatCompound No. 27 inhibits target HER2 S310F mutant kinase activity.

EQUIVALENTS

The details of one or more embodiments of the disclosure are set forthin the accompanying description above. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, the preferred methodsand materials are now described. Other features, objects, and advantagesof the disclosure will be apparent from the description and from theclaims. In the specification and the appended claims, the singular formsinclude plural referents unless the context clearly dictates otherwise.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. All patents and publicationscited in this specification are incorporated by reference.

The foregoing description has been presented only for the purposes ofillustration and is not intended to limit the disclosure to the preciseform disclosed, but by the claims appended hereto.

1. A compound or pharmaceutically acceptable salts or stereoisomersthereof of formula I

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4 Y² isa covalent bond, —O—, —NH—, —NCH₃—, or —C≡C—; Z is —(NR⁶R⁷), —(CHR⁶R⁷),wherein R⁶ and R⁷ form together with the atom to which they are attachedto

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; X⁷ is —O—, —NH—, —N(CH₃)—,or —SO₂; R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; wherein R^(a) andR^(b) are independently of each other H or —CH₂—O—CH₃; X is a group offormula (i)a

wherein X¹ is —O—, —CH₂—, —NH—, or —S—; Ar¹ is 6 membered aryl orN-heteroaryl, which is unsubstituted or substituted with one or more ofa group selected from hal, C₁₋₆alkyl, or C₁₋₆alkoxy; Ar² is 6 memberedaryl or N-heteroaryl, which is unsubstituted or substituted with one ormore of a group selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, —CF₃, or—OCF₃; and L¹ is a covalent bond or straight or branched C₁₋₃alkyl,which is unsubstituted or substituted with hal.
 2. (canceled)
 3. Thecompound of claim 1 or pharmaceutically acceptable salts orstereoisomers thereof, wherein L¹ is covalent bond, —CH₂—, —CH(CH₃)—,CH(hal)-, —CH₂—CH₂—, —CH₂—CH(CH₃)—, or —CH₂—CH(hal)-.
 4. The compound ofclaim 1 or pharmaceutically acceptable salts or stereoisomers thereof,wherein R^(a) and R^(b) are hydrogen.
 5. (canceled)
 6. The compound ofclaim 1 or pharmaceutically acceptable salts or stereoisomers thereof,wherein X¹-L¹ is —O—, —CH₂—, —O—CH₂—, —NH—CH₂—, —S—CH₂—, —CH₂—CH₂—,—O—CH(CH₃)—, —CH₂—CH(CH₃)—, —NH—CH(CH₃)—, —S—CH(CH₃)—, —O—CH(hal)-,—CH₂—CH(hal)-, —NH—CH(hal)-, or —S—CH(hal).
 7. (canceled)
 8. Thecompound of claim 1 or pharmaceutically acceptable salts orstereoisomers thereof, wherein X is a group of formula (ii)a,

wherein X¹ is —O—, —CH₂—, —NH—, or —S—; L¹ is a covalent bond orC₁₋₃alkyl, which is unsubstituted or substituted with —CH₃, or hal; X²,X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently of each other—N═ or —CH═; and R², R^(2′), R³, and R^(3′) are independently of eachother H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃.
 9. The compound of claim 1 orpharmaceutically acceptable salts or stereoisomers thereof wherein X isa group of formula (ii)b, (ii)b-1, (ii)b-2, (ii)c, (ii)c-1, or (ii)c-2

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently ofeach other —N═ or —CH═; R², R^(2′), R³, and R^(3′) are independently ofeach other H, C₁₋₆ alkyl, hal, —CF₃, or —OCF₃; and n is 0, 1, 2, or 3.10.-15. (canceled)
 16. The compound of claim 1 or pharmaceuticallyacceptable salts or stereoisomers thereof, wherein X is

wherein R² and R^(2′) are independently of each other H, C₁₋₆alkyl, orhal; R³ and R^(3′) are independently of each other H, C₁₋₆alkyl, hal,—CF₃, or —OCF₃; and n is 0 or
 1. 17. (canceled)
 18. The compound ofclaim 1 or pharmaceutically acceptable salts or stereoisomers thereof,wherein the compound is of formula II or III

wherein L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4; Y²is a covalent bond, —O—, —NH—, —NCH₃—, or —C≡C—; Z is

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; X⁷ is —O—, —NH—, —N(CH₃)—,or —SO₂; R^(a) and R^(b) are independently of each other H or—CH₂—O—CH₃; X is a group of formula (ii)a

wherein X¹ is —O—, —CH₂—, or S; L¹ is a covalent bond or C₁₋₃alkyl,which is unsubstituted or substituted with —CH₃ or hal; X², X^(2′), X³,X^(3′), X⁵, X^(5′), and X⁶ are independently of each other —N═ or —CH═;and R², R^(2′), R³, and R^(3′) are independently of each other H, C₁₋₆alkyl, hal, —CF₃, or —OCF₃.
 19. The compound of claim 1 orpharmaceutically acceptable salts or stereoisomers thereof, wherein thecompound is of formula IV

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently ofeach other —N═ or —CH═; X¹ is —O—, —CH₂—, or —NH—; L¹ is a covalent bondor straight chain or branched C₁₋₃alkyl, which is unsubstituted orsubstituted with hal; R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; whereinR^(a) and R^(b) are independently of each other H or —CH₂—O—CH₃; R²,R^(2′), R³, and R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, or —OCF₃; L is a covalent bond, straight chain or branchedC₁₋₄ alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4; Z is

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; and X⁷ is —O—, —NH—,—N(CH₃)—, or —SO₂.
 20. The compound of claim 1 or pharmaceuticallyacceptable salts or stereoisomers thereof, wherein the compound is offormula VII

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently ofeach other —N═ or —CH═; X¹ is —O—, —CH₂—, —NH—, or —S—; L¹ is a covalentbond or straight chain or branched C₁₋₃alkyl, which is unsubstituted orsubstituted with hal; R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; whereinR^(a) and R^(b) are independently of each other H or —CH₂—O—CH₃; R²,R^(2′), R³, and R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, or —OCF₃; L is a covalent bond, straight chain or branchedC₁₋₄ alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4; Z is

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; and X⁷ is —O—, —NH—,—N(CH₃)—, or —SO₂.
 21. The compound of claim 1 or pharmaceuticallyacceptable salts or stereoisomers thereof, wherein the compound is offormula X

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently ofeach other —N═ or —CH═; X¹ is —O—, —CH₂—, —NH—, or —S—; L¹ is a covalentbond or straight chain or branched C₁₋₃alkyl, which is unsubstituted orsubstituted with hal; R¹ is —CR_(b)═CHR_(a), —C≡CH or —C≡C—CH₃; whereinR^(a) and R^(b) are independently of each other H or —CH₂—O—CH₃; R²,R^(2′), R³, and R^(3′) are independently of each other H, C₁₋₆ alkyl,hal, —CF₃, —OCF₃; L is a covalent bond, straight chain or branched C₁₋₄alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4; R′″is H or —CH₃; and Z is

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; and X⁷ is —O—, —NH—,—N(CH₃)—, or —SO₂.
 22. The compound of claim 1 or pharmaceuticallyacceptable salts or stereoisomers thereof, wherein the compound is offormula XIII

wherein X², X^(2′), X³, X^(3′), X⁵, X^(5′), and X⁶ are independently ofeach other —N— or —CH—; X¹ is —O—, —CH₂—, —NH—, or —S—; L¹ is a covalentbond or straight chain or branched C₁₋₃alkyl, which is unsubstituted orsubstituted with hal; R¹ is —CH═CH₂, —C≡CH or —C≡C—CH₃; R², R^(2′), R³,and R^(3′) are independently of each other H, C₁₋₆ alkyl, hal, —CF₃, or—OCF₃; L is a covalent bond, straight chain or branched C₁₋₄ alkyl or

wherein m1 and m2 are independently of each other 0, 1, 2, 3, or 4; Z is

R^(c) is H, C₁₋₄ alkyl, or oxetane; R^(d) is H or C₁₋₄ alkyl; X⁶ is H,—CH₃, —OH, —OCH₃, —OCF₃, —N(CH₃)₂, F, or Cl; and X⁷ is —O—, —NH—,—N(CH₃)—, or —SO₂.
 23. (canceled)
 24. A compound selected from thecompounds described in Table I and pharmaceutically acceptable saltsthereof.
 25. (canceled)
 26. A composition comprising the compound ofclaim 1 or pharmaceutically acceptable salts or stereoisomers thereof,and one or more pharmaceutically acceptable carrier. 27.-31. (canceled)32. A method of preventing or treating cancer, comprising administeringto the subject in need thereof a therapeutically effective amount of thecompound of claim
 1. 33. A method of preventing or treating cancer,comprising administering to the subject in need thereof the compositionof claim
 26. 34.-412. (canceled)
 113. The method of claim 32, whereinthe cancer comprises a solid tumor.
 114. The method of claim 32, whereinthe cancer is a bladder cancer, a breast cancer, a cervical cancer, acolorectal cancer, an endometrial cancer, a gastric cancer, aglioblastoma (GBM), a head and neck cancer, a lung cancer, a non-smallcell lung cancer (NSCLC) or any subtype thereof. 115.-141. (canceled)142. The method of claim 33, wherein the cancer comprises a solid tumor.143. The method of claim 33, wherein the cancer is a bladder cancer, abreast cancer, a cervical cancer, a colorectal cancer, an endometrialcancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer,a lung cancer, a non-small cell lung cancer (NSCLC) or any subtypethereof.